JP2003342283A - Nucleotide analogue compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain adefovir dipivoxil (AD) having a good melting point and/or flow characteristics or density characteristics for facilitating the production and formulation of a composition containing the AD, having a stable form for its storage, immediately filtrable and easily dried, having at least approximately 97% (wt/wt) purity, preferably at least approximately 98% purity, a composition containing a new form AD having a desirable properties for a large scale synthesis or the formulation for a therapeutic administration, and a method for purifying capable of removing or minimizing byproducts produced during the AD synthesis and not using a column chromatography which is expensive and time consuming. <P>SOLUTION: The composition contains the crystalline adefovir dipivoxil. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION The present invention relates to the nucleotide analog 9- [2-[[bis [(pivaloyloxy) -methoxy] phosphinyl] methoxy] ethyl] adenine (“adefovir dipivoxil”).
ipivoxil) "or" AD "), and uses thereof. The invention also relates to a method of synthesizing AD.

[0002]

AD is the bis-form of the parent compound 9- [2- (phosphonomethoxy) ethyl] adenine ("PMEA").
Pivaloyloxymethyl ester, which has antiviral activity in animals and in humans.
AD and PMEA have been described, for example, in US Pat. Nos. 4,724,233 and 4,808,716, European Patent Nos. 481,214.
No., Benzaria et al., Nucleosides a
nd Nucleotides (1995) 14 (3
~ 5): 563-565, Holy et al., Collec.
t. Czech. Chem. Commun. (198
9) 54: 219-2021, Holy et al., Coll.
ect. Czech. Chem. Commun. (19
87) 52: 2801-2809, Rosenberg.
Et al., Collect. Czech. Chem. Comm
un. (1988) 53: 2753-2777, Sta.
rrett et al., Antiviral Res. (199
2) 19: 267-273; Starrett et al.
Med. Chem. (1994) 37: 1857-18
64. So far, AD has been provided only as an amorphous or amorphous form. It has not been reported to be prepared as a crystalline material.

Methods for crystallizing organic compounds by themselves are described in J. A. Landgrebe, Theory
and Practice in the Orga
nic Laboratory, 2nd edition, 1977,
D. C. Heat and Co. , Lexingto
n, MA, pp. 43-51; S. Myerson, H
andbook of Industrial Cry
stallization, 1993, Butterw
orth-Heinemann, Stoneham, M
A, pages 1-101).

[0004]

The present invention provides one or more compositions or methods that meet one or more of the following objects.

The main object of the present invention is to provide a composition containing a novel form of AD which has desirable properties for large scale synthesis or for formulation into therapeutic dosing.

Another object is to provide an AD with good melting point and / or rheological or bulk density characteristics that facilitates the manufacture and formulation of compositions containing AD.

Another object is to provide a storage stable form of AD.

Another object is to provide an AD which can be filtered immediately and dried easily.

Another object is to have at least about 97% (w /
w), and preferably a high purity AD having a purity of at least about 98%.

Another object is to eliminate or minimize the by-products created during AD synthesis.

Another object is to provide a method for purifying AD that does not use expensive and time consuming column chromatography.

The present invention accomplishes its main purpose by providing crystalline AD, and in particular by providing the following forms: anhydrous crystalline form (hereinafter "Form 1"), hydrated form C _{20 H 32 N 5 O 8 P} 1 · 2H 2 O
(Hereinafter “form 2”), methanol solvated C ₂₀ H _{32
N 5 O 8 P 1 · CH} 3 OH ( hereafter "Form 3"), fumarate or complex _{C 20 H 32 N 5 O 8} P 1 · C 4 H 4
O ₄ (hereinafter “form 4”), hemisulphate (hemisul)
fate) or complex, hydrobromide or complex,
Hydrochloride or complex, nitrate or complex, mesylate (CH ₃ SO ₃ H) salt or complex, ethyl sulfonate (C ₂ H ₅ SO ₃ H) or complex, β-naphthylene sulfonate or complex Body, α-naphthylene sulfonate or complex, (S) -camphor sulfonate or complex, succinate or complex, maleate or complex, ascorbate or complex, and nicotinate Or a complex.

Embodiments of the invention include the following: (1)
Using Cu-Kα irradiation, at an angle 2θ, about 6.9, about 1
1.8, about 12.7, about 15.7, about 17.2, about 2
Essentially having a powder X-ray diffraction ("XRD") spectrum that appears (in any combination) in any one or more of 0.7, about 21.5, about 22.5, and about 23.3, Crystalline form 1 AD; (2) using Cu-Kα irradiation, corner 2
θ, about 8.7 to 8.9, about 9.6, about 16.3, about 1
8.3, about 18.9, about 19.7, about 21.0, about 2
1.4, about 22.0, about 24.3, about 27.9, about 3
Essentially having an XRD spectrum that appears (in any combination) at any one or more of 0.8 and about 32.8,
Crystalline form 2 AD; (3) using Cu-Kα irradiation,
At an angle 2θ of about 8.1, about 8.7, about 14.1, about 16.
5, about 17.0, about 19.4, about 21.1, about 22.
6, about 23.4, about 24.2, about 25.4, and about 3
X appearing in any one or more of 0.9 (in any combination)
Crystalline Form 3 A having essentially an RD spectrum
D; and using Cu-Kα irradiation at an angle 2θ of about 9.8, about 15.2, about 15.7, about 18.1, about 1.
AD of crystalline form 4, essentially having an XRD spectrum that appears (in any combination) in any one or more of 8.3, about 21.0, about 26.3, and about 31.7.

Embodiments of the present invention include AD crystals having the crystal morphology shown in any one or more of FIGS.

In another embodiment, the present invention comprises about 6 to
Contains 45% AD and about 55-94% crystallization solvent
AD crystals by which crystals can be formed from a crystallization solution
To provide a crystallization solvent in which the crystallization solvent is a group consisting of
Selected from: (1) about 1:10 v / v and about 1: 3 v
Acetone: di-n-butyl ether
Compound, (2) between about 1:10 v / v and about 1: 3 v / v
A mixture of ethyl acetate: di-n-propyl ether,
(3) between about 1:10 v / v and about 10: 1 v / v,
a mixture of t-butanol: di-n-butyl ether,
(4) Salt between about 1:10 v / v and about 1: 3 v / v
A mixture of methylene chloride: di-n-butyl ether, (5)
Diet between about 1:10 v / v and about 10: 1 v / v
Ruether: a mixture of di-n-propyl ether,
(6) between about 1:10 v / v and about 1: 3 v / v,
A mixture of trahydrofuran: di-n-butyl ether,
(7) Vinegar between about 1:10 v / v and about 1: 3 v / v
A mixture of ethyl acid: di-n-butyl ether, (8)
Tetrahydr between 1:10 v / v and about 1: 3 v / v
A mixture of ropyran: di-n-butyl ether, (9)
Ethyl acetate between 1:10 v / v and about 1: 3 v / v
Mixture of: diethyl ether, (10) t-butyl-
Methyl ether, (11) Diethyl ether, (12)
Di-n-butyl ether, (13) t-butanol,
(14) Toluene, (15) Isopropyl acetate, (1
6) Ethyl acetate, (17) A mixture consisting essentially of:
Object: (A) Formula R¹-OR^TwoThe first dialkyl ether
A first crystallization solvent consisting of R, where R¹Is 1, 2,
Alkyl groups having 3, 4, 5, or 6 carbon atoms
And R^TwoIs 2, 3, 4, 5, or 6 carbon atoms
An alkyl group having R, or R ¹And R^TwoWith
Both are connected together and are joined by five, six, seven,
Forms an eight-membered ring, except that dialkyl ether
Not tyl-ethyl ether, and (B) from below
A second crystallization solvent selected from the group consisting of: (a) Formula R¹
-OR^TwoThe second dialkyl ether of, where the second
Dialkyl ether is different from the first dialkyl ether
However, it is not methyl ethyl ether,
(B) Toluene, (c) Tetrahydrofuran, (d) t
-Butanol, (e) ethyl acetate, (f) methyl chloride
, (G) propyl acetate, and (h) isopropano
Le.

Embodiments of the invention include purified crystalline AD (eg, Form 1 and / or Form 2). Embodiments of the present invention also include crystalline AD (eg, Form 1 and / or
Or Form 2) and one or more compounds (such as a pharmaceutical excipient or a compound present in a reaction mixture containing crystalline AD).

An embodiment of the present invention comprises the steps of dissolving AD in methanol and allowing crystals to form.
Includes methods for producing AD crystals.

Another embodiment is a pharmaceutical composition, or crystalline AD suitable for use, including: retroviral infection (HIV, S, eg in humans or animals).
IV, FIV), or hepatitis B virus, or other hepadnavirus infections,
Or DNA virus infection (human cytomegalovirus or herpes virus, such as HSV1 or HS
One or more Form 1, Form 2, Form 3 and / or Form 4 AD for treating viral conditions in which PMEA is known to be active, such as V2), and a pharmaceutical Acceptable carrier.

The present invention provides a method for producing crystalline Form 2 AD which comprises the step of forming AD crystals in the presence of water.

In another embodiment, the method for preparing AD comprises the step of adding PMEA to N-methylpyrrolidinone (NM
P, 1-methyl-2-pyrrolidinone) and contact with a trialkylamine such as chloromethylpivalate and triethylamine (TEA), and recovering AD.

In a further embodiment, there is provided a PMEA composition comprising less than about 2% salt, which may be used in a method comprising contacting PMEA comprising less than about 2% salt.

In a further embodiment, liquid, Form 1
AD product is obtained by a process comprising the steps of preparing wet granules from a mixture comprising adefovir dipivoxil of, and an acceptable excipient, and optionally drying the wet granules.

[0023]

The present invention includes a composition comprising crystalline adefovir dipivoxil.

In one embodiment, the present invention provides a composition wherein the crystalline adefovir dipivoxil is the anhydrous crystalline form adefovir dipivoxil.

In one embodiment, there is provided a composition comprising a C-center monoclinic lattice substantially as specified below: a = 12.85Å, b = 24.50Å, c = 8.
28Å, β = 100.2 °, Z = 4, space group Cc.

In one embodiment, Cu-Kα irradiation is used to provide a composition having an X-ray powder diffraction spectrum peak appearing at 6.9 at an angle 2θ.

In one embodiment, D at about 102 ° C.
A composition having an SC endothermic transition is provided.

[0028] In one embodiment, the crystalline adduct
Fovir dipivoxil is hydrated, C ₂₀H₃₂N₅O₈
P ・ 2H_TwoA composition that is adefovir dipivoxil of O.
I will provide a.

In one embodiment, using Cu-Kα irradiation, the X-ray powder diffraction spectral peaks appearing at about 9.6, about 18.3, about 22.0, and about 32.8 at angle 2θ. There is provided a composition having:

In one embodiment, the DS at about 73.degree.
A composition having a C endothermic transition is provided.

In one embodiment, the crystalline adefovir dipivoxil is methanol solvated, C ₂₀ H
_A composition is provided that is adefovir dipivoxil of ₃₂ N ₅ O ₈ P.CH ₃ OH.

In one embodiment, the X-ray powder diffraction spectrum peaks appearing at about 8.1, about 19.4, about 25.4, and about 30.9 at angle 2θ using Cu-Kα irradiation. There is provided a composition having:

In one embodiment, the DS at about 85.degree.
A composition having a C endothermic transition is provided.

In one embodiment, the crystalline adefovir dipivoxil is a fumarate or complex, C
Provided is a composition that is adefovir dipivoxil of ₂₀ H ₃₂ N ₅ O ₈ P.C ₄ H ₄ O ₄ .

In one embodiment, the X-ray powder diffraction spectrum peaks appearing at about 9.8, about 15.2, about 26.3, and about 31.7 at an angle 2θ using Cu-Kα irradiation. There is provided a composition having:

In one embodiment, the D at about 148.degree.
A composition having an SC endothermic transition is provided.

In one embodiment, a composition comprising a crystalline salt of adefovir dipivoxil is provided.

In one embodiment, a composition is provided wherein the crystalline salt is a salt of an organic acid.

In one embodiment, a composition is provided wherein the crystalline salt is a salt of an inorganic acid.

In one embodiment, the crystalline adefovir dipivoxil is hemisulfate, hydrobromide, hydrochloride, nitrate, mesylate, ethanesulfonate, β-
Crystalline salt of adefovir dipivoxil selected from the group consisting of naphthylene sulfonate, α-naphthylene sulfonate, (S) -camphor sulfonate, succinic acid, maleic acid, ascorbic acid, or nicotinic acid. Is provided.

In one embodiment, a composition comprising a pharmaceutically acceptable excipient is provided.

The present invention provides a method comprising the step of administering to a subject an antivirally effective amount of the above composition.

The present invention includes a method which includes the step of contacting adefovir dipivoxil with a crystallization solvent.

In one embodiment, a method is provided wherein the adefovir dipivoxil is in solution.

In one embodiment, the crystallization solvent is mixed with the solution to obtain a second solution, which provides a method of forming crystals.

The present invention is a process comprising crystallization of adefovir dipivoxil from a solution containing about 6-45% adefovir dipivoxil and 55-94% crystallization solvent, wherein the crystallization solvent is Includes a method selected from the group consisting of: (1) about 1:10 v / v
And a mixture of acetone: di-n-butyl ether between about 1: 3 v / v and (2) about 1:10 v / v and about 1: 3.
a mixture of ethyl acetate: di-n-propyl ether between v / v, (3) about 1:10 v / v and about 10: 1 v / v.
a mixture of t-butanol: di-n-butyl ether between v and (4) a mixture of methylene chloride: di-n-butyl ether between about 1:10 v / v and about 1: 3 v / v, (5) A mixture of diethyl ether: di-n-propyl ether between about 1:10 v / v and about 10: 1 v / v, (6) about 1:10 v / v and about 1: 3 v / v. A mixture of tetrahydrofuran: di-n-butyl ether, (7) a mixture of ethyl acetate: di-n-butyl ether between about 1:10 v / v and about 1: 3 v / v,
(8) A mixture of tetrahydropyran: di-n-butyl ether between about 1:10 v / v and about 1: 3 v / v,
(9) a mixture of ethyl acetate: diethyl ether between about 1:10 v / v and about 1: 3 v / v, (10) t-butyl-methyl ether, (11) diethyl ether,
(12) di-n-butyl ether, (13) t-butanol, (14) toluene, (15) isopropyl acetate,
(16) Ethyl acetate, and (17) a mixture consisting essentially of: (A) a first crystallization solvent consisting of a first dialkyl ether of the formula R ¹ —O—R ² , where R ¹ is 1. An alkyl group having 2, 3, 4, 5, or 6 carbon atoms, R ² is an alkyl group having 2, 3, 4, 5, or 6 carbon atoms, and R ¹ and R ² Are the same or different, or both R ¹ and R ² are joined together to form a 5-, 6-, 7-, or 8-membered ring, provided that the dialkyl ether is not methyl-ethyl ether , And (B) a second crystallization solvent selected from the group consisting of: (a) a second dialkyl ether of formula R ¹ —O—R ² , wherein the second dialkyl ether is the first dialkyl Different from ether,
(B) Toluene, (c) Tetrahydrofuran, (d) t
-Butanol, (e) ethyl acetate, (f) methylene chloride, (g) propyl acetate, and (h) isopropanol.

The present invention comprises the step of forming crystals of adefovir dipivoxil in the presence of water, the hydrated form, C _20.
In one embodiment, including a method for preparing adefovir dipivoxil of H ₃₂ N ₅ O ₈ P · 2H ₂ O, in the hydrated form, C ₂₀ H ₃₂ N ₅ O ₈ P · 2H ₂ O.
Adefovir dipivoxil of (1) hydrating crystals of anhydrous crystalline form of adefovir dipivoxil and / or (2) crystallizing adefovir dipivoxil in the presence of water. provide.

The present invention comprises the step of forming a crystal containing adefovir dipivoxil in the presence of fumaric acid, a fumarate or complex, C ₂₀ H ₃₂ N ₅ O ₈ P ₁ .C _4.
A method for preparing adefovir dipivoxil of H ₄ O ₄ is included.

In one embodiment, the present invention provides a 9-
[2- (phosphonomethoxy) ethyl] adenine was converted into 1-
Provided is a method for preparing adefovir dipivoxil, comprising contacting with chloromethyl pivalate and trialkylamine in methyl-2-pyrrolidinone, and recovering adefovir pivaloxyl.

In one embodiment, a method is provided wherein the trialkylamine is triethylamine.

In one embodiment, one molar equivalent of 9
A method is provided that comprises contacting-[2- (phosphonomethoxy) ethyl] adenine with about 5.6 to 56.8 molar equivalents of 1-methyl-2-pyrrolidinone.

In one embodiment, one molar equivalent of 9
-[2- (phosphonomethoxy) ethyl] adenine is provided with a step of contacting about 2-5 molar equivalents of triethylamine.

The present invention provides 9- [2 containing less than about 2% salt.
The method comprises the step of contacting-(phosphonomethoxy) ethyl] adenine with chloromethyl pivalate.

In one embodiment, the salt is NaB
The method is r or KBr.

The present invention includes products made by the process of compressing a mixture comprising anhydrous crystalline form adefovir dipivoxil and a pharmaceutically acceptable excipient.

In one embodiment, the compression provides a product which results in a tablet.

The product of the present invention comprises a wet granule product prepared by the process of preparing a wet granule from a mixture comprising a liquid, an anhydrous crystalline form of adefovir dipivoxil, and a pharmaceutically acceptable excipient. Include.

In one embodiment, the product is provided wherein the liquid is water.

In one embodiment, the above process further provides a product comprising the step of drying the wet granules.

The present invention relates to adefovir dipivoxil, 2
A composition comprising a tablet comprising 0 mg pregelatinized starch, 24 mg croscarmellose sodium, lactose monohydrate, 24 mg talc, and 4 mg magnesium stearate, wherein the adefovir dipivoxil is A composition comprising at least about 70% anhydrous crystalline form of adefovir dipivoxil is included.

In one embodiment, the tablets are 60
Provided is a composition comprising mg adefovir dipivoxil and 268 mg lactose monohydrate.

In one embodiment the tablet comprises about 4
Provided is the described composition, which weighs 00 mg.

In one embodiment, there is provided a composition wherein said adefovir dipivoxil comprises at least about 80% anhydrous crystalline form of adefovir dipivoxil.

In one embodiment, the tablets are 12
A composition comprising 0 mg adefovir dipivoxil and 208 mg lactose monohydrate is provided.

In one embodiment, the tablet comprises about 4
A composition is provided that weighs 00 mg.

In one embodiment, there is provided a composition wherein the adefovir dipivoxil comprises at least 80% anhydrous crystalline form of adefovir dipivoxil.

The present invention includes a method for preparing 9- [2- (diethylphosphonomethoxy) ethyl] adenine comprising the step of contacting sodium alkoxide and 9- (2-hydroxyethyl) adenine.

[0068]

DETAILED DESCRIPTION OF THE INVENTION Temperatures are in degrees Celsius (° C.) unless otherwise indicated. Room temperature means about 18-23 ° C.

As used herein, alkyl
Means linear, branched, and cyclic saturated hydrocarbons.
“Alkyl” or “alkyl moiety” are used herein
As used, unless otherwise stated
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or
Or 12 normal, secondary, tertiary or ring structures
It is a hydrocarbon containing structure. Term C₁~₁₀Alkyl is
1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
It means an alkyl group having a carbon atom. An example is -CH
_Three, -CH_TwoCH_Three, -CH_TwoCH_TwoCH_Three, -CH
(CH_Three)_Two, -CH_TwoCH_TwoCH_TwoCH_Three, -CH_Two
CH (CH_Three)_Two, -CH (CH_Three) CH_TwoCH_Three,-
C (CH_Three)_Three, -CH_TwoCH_TwoCH_TwoCH_TwoCH_Three,
-CH (CH _Three) CH_TwoCH_TwoCH_Three, -CH (CH_Two
CH_Three)_Two, -C (CH_Three)_TwoCH_TwoCH_Three, -CH
(CH_Three) CH (CH_Three)_Two, -CH_TwoCH_TwoCH (C
H_Three)_Two, -CH_TwoCH (CH_Three) CH_TwoCH_Three, -C
H_TwoC (CH_Three)_Three, -CH_TwoCH_TwoCH_TwoCH_TwoCH
_TwoCH_Three, -CH (CH_Three) CH_TwoCH_TwoCH_TwoC
H_Three, -CH (CH_TwoCH_Three) (CH_TwoCH_TwoC
H_Three), -C (CH_Three)_TwoCH_TwoCH _TwoCH_Three, -CH
(CH_Three) CH (CH_Three) CH_TwoCH_Three, -CH (CH
_Three) CH_TwoCH (CH_Three)_Two, -C (CH_Three) (CH_Two
CH_Three)_Two, -CH (CH_TwoCH_Three) CH (C
H_Three)_Two, -C (CH_Three)_TwoCH (CH_Three)_Two, -CH
(CH_Three) C (CH_Three)_Three, Cyclopropyl, cyclobu
Chill, cyclopropylmethyl, cyclopentyl, cyclo
Butylmethyl, 1-cyclopropyl-1-ethyl, 2-
Cyclopropyl-1-ethyl, cyclohexyl, cyclo
Pentylmethyl, 1-cyclobutyl-1-ethyl, 2-
Cyclobutyl-1-ethyl, 1-cyclopropyl-1-
Propyl, 2-cyclopropyl-1-propyl, 3-si
Clopropyl-1-propyl, 2-cyclopropyl-2
-Propyl, and 1-cyclopropyl-2-propyl
Is.

“Alkoxide” is used herein.
Oxygen atom, unless stated otherwise.
As defined herein for alkyl, linked to
1, 2, 3, 4, 5, or 6 carbon atoms as
It is a hydrocarbon containing. Example is -OCH_Three, -OCH_Two
CH_Three, -OCH_TwoCH_TwoCH_Three, -OCH (CH_Three)
_Two, -OCH_TwoCH_TwoCH_TwoCH_Three, -OCH_TwoCH
(CH_Three)_Two, -OCH (CH_Three) CH_TwoCH_Three, -O
C (CH_Three)_Three, -OCH_TwoCH_TwoCH_TwoCH _TwoC
H_Three, -OCH (CH_Three) CH_TwoCH_TwoCH_Three, -OC
H (CH_TwoCH_Three) _Two, -OC (CH_Three)_TwoCH_TwoCH
_Three, -OCH (CH_Three) CH (CH_Three)_Two, -OCH_Two
CH_TwoCH (CH_Three)_Two, -OCH_TwoCH (CH_Three) C
H_TwoCH_Three, -OCH_TwoC (CH_Three)_Three, -OCH (C
H_Three) (CH_Two)_ThreeCH_Three, -OC (CH_Three)_Two(CH
_Two)_TwoCH_Three, -OCH (C_TwoH₅) (CH_Two)_TwoCH
_Three, -O (CH_Two)_ThreeCH (CH_Three)_Two, -O (C
H_Two)_TwoC (CH_Three)_Three, -OCH _TwoCH (CH_Three)
(CH_Two)_TwoCH_Three, And -OCH_TwoCH_TwoCH_TwoC
H_TwoCH_TwoCH_ThreeIs.

"Trialkylamine" is 3 C₁~
₆Means nitrogen atoms substituted with alkyl moieties, those
Are independently selected. Examples are 1, 2, or 3
-CH_Three, -CH_TwoCH_Three, -CH_TwoCH_TwoCH_Three,-
CH (CH_Three)_Two, -CH_TwoCH_TwoCH_TwoCH_Three, -C
H_TwoCH (CH_Three)_Two, -CH (CH_Three) CH_TwoC
H _Three, -C (CH_Three)_Three, -CH_TwoCH_TwoCH_TwoCH_Two
CH_Three, -CH (CH_Three) CH_TwoCH_TwoCH_Three, -CH
(CH_TwoCH_Three)_Two, -C (CH_Three)_TwoCH_TwoCH _Three,
-CH (CH_Three) CH (CH_Three)_Two, -CH_TwoCH_TwoC
H (CH_Three)_Two, -CH_TwoCH (CH_Three) CH_TwoC
H_Three, -CH_TwoC (CH_Three)_Three, -CH_TwoCH_TwoCH_Two
CH_TwoCH_TwoCH_Three, -CH (CH_Three) CH_TwoCH_TwoC
H_TwoCH_Three, -CH (CH_TwoCH_Three) (CH_TwoCH_TwoC
H_Three), -C (CH_Three)_TwoCH_TwoCH_TwoCH_Three, -CH
(CH_Three) CH (CH_Three) CH_TwoCH_Three, -CH (CH
_Three) CH_TwoCH (CH_Three)_Two, -C (CH_Three) (CH_Two
CH_Three)_Two, -CH (CH_TwoCH_Three) CH (C
H_Three)_Two, -C (CH_Three)_TwoCH (CH_Three)_Two, Or
-CH (CH _Three) C (CH_Three)_ThreeNitrogen partially substituted
Is.

As used herein, "heteroaryl" includes those heterocycles described below by way of example and not limitation: Paquette,
Leo A. Principles of Mod
ern Heterocyclic Chemistr
y (WA Benjamin, New York,
1968), especially chapters 1, 3, 4, 6, 7, and 9;
The Chemistry of Heterocy
CLICK COMPUNDS, A series
of Monographs (John Wiley
& Sons, New York, 1950-to date), especially Volumes 13, 14, 16, 19, and 28;
And J. Am. Chem. Soc. , (1960) 8
2: 5566.

Examples of heterocyclic rings include, by way of example and without limitation, pyridyl, thiazolyl, tetrahydrothiophenyl, tetrahydrothiophenyl sulfur oxide, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, Benzofuranyl, thianaphthalenyl, indolyl, indenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydro. Isoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H, 6H-1,5,2-dithiazinyl, thienyl, thianthreni (Thianthrenyl), pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl alkenyl, 2H- pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, 1H
-Indazolyl, purinyl, 4H
-Quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, b-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, isophenazinyl, phenoxazinyl, phenoxazinyl, phenazolinyl, phenazolinyl. Chromanil, imidazolidinyl, imidazolinyl,
Pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxyindolyl, benzoxazolinyl, and isatinoyl.

By way of example, and not limitation, the carbon-bonded heterocycle is attached at the following positions: position 2, 3, 4, 5, or 6 of pyridine, 3, 4, of pyridazine.
The 5 or 6 position, the pyrimidines 2, 4, 5 or 6
Position, 2, 3, 5 or 6 position of pyrazine, furan, tetrahydrofuran, thiofuran, thiophene, pyrrole,
Or 2, 3, 4, or 5 of tetrahydropyrrole
Position, 2, 4, or 5 position of oxazole, imidazole, or thiazole, 3, 4, or 5 position of isoxazole, pyrazole, or isothiazole, 2 or 3 position of aziridine, 2, 3, or 4 position of azetidine, Position 2,3,4,5,6,7 or 8 of quinoline or 1,3,4,5,6,7 or 8 of isoquinoline
Rank. Even more typically, the carbon-bonded heterocycle is 2-
Pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, Includes 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example, and not limitation, nitrogen bonded heterocycles are attached at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-
Pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,
2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1-position of 1H-indazole, 2-position of isoindole or isoindoline, 4-position of morpholine, and 9-position of carbazole or β-carboline. Even more typically, the nitrogen-bonded heterocycle is 1-aziridyl, 1-azetedyl.
1), 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

As used herein, AD or “crystalline material”, “crystalline”, or “crystalline” refers to
By solid AD is meant that substantially all constituent molecules (s) have an ordered array in a three-dimensional spatial pattern or lattice. Crystalline or crystalline AD is
One or more than one composition, eg AD.
It may include fumaric acid or AD · 2H ₂ O. A crystalline material or crystal is one or more than one crystal habit,
For example, it can occur in tablets, columns, plates, or needles.

Unless explicitly stated otherwise or in the context, percentage amounts are expressed as% by weight (w / w). Thus, a solution containing at least about 40% AD is a solution containing at least about 40% w / w AD. Solid AD with 0.1% water means 0.1% w / w water with solids.

Crystalline AD substantially free of amorphous AD
Means a solid composition in which more than about 60% AD is present in the composition as a crystalline material. Such compositions typically include at least about 80%, usually at least about 90%, of more than one AD crystalline form, with the remaining AD present as amorphous AD.

The composition of the present invention is, if desired, used in the present specification.
Includes salts of the compounds in the text, which may be charged, for example.
Not Acceptable or Containing Monovalent Anion
Contains noble salt. The salt (s) can be inorganic or organic
Induced by the combination of appropriate anions such as organic acids
Including things. Suitable acid is sufficient to form a stable salt
Those having various acidic properties, preferably low-toxic acid. An example
For example, certain organic and inorganic acids such as HF, HCl,
HBr, HI, H_TwoSO_Four, H_ThreePO_FourOr organic
Basic center of sulfonic acid and organic carboxylic acid, typically
Acid additions to amines may form salts of this invention. Illustrative
Organic sulfonic acids are C₆~₁₆Aryl
Sulfonic acid, C₆~₁₆Heteroaryl sulfonic acid,
And C₁~₁₆Alkyl sulfonic acid (eg, phenyl
, Α-naphthyl, β-naphthyl, (S) -camphor
-, Methyl, ethyl, n-propyl, i-propyl, n
-Butyl, s-butyl, i-butyl, t-butyl, pen
Chill, and hexyl sulfonic acid). Exemplifying
Carboxylic acid is the following C₁~₁₆Alkyl, C
₆~₁₆Aryl carboxylic acid, and C_Four~₁₆Hetero
Aryl carboxylic acids (eg acetic acid, glycolic acid, milk
Acid, pyruvic acid, malonic acid, glutaric acid, tartaric acid, queer
Acid, fumaric acid, succinic acid, malic acid, maleic acid, hyaluronic acid
Droxymaleic acid, benzoic acid, hydroxybenzoic acid,
Phenylacetic acid, cinnamic acid, salicylic acid, and 2-phene
(Noxybenzoic acid). Salt is also one or more amino
Includes salts of the compounds of the present invention with acids. Many amino acids, special
Is a naturally occurring protein found in
Amino acids are typically basic, although mino acids are suitable.
Or those having a side chain with an acidic group (eg
, Arginine, or glutamic acid), or neutral
Having a side chain with a group (eg, glycine, serine
, Threonine, alanine, isoleucine, or leuine
Shin). Salts are usually specifically directed against mammalian cells.
And biocompatible or pharmaceutically acceptable
Or is non-toxic. Biologically toxic
Salts are generally used with synthetic intermediates of compounds of the invention.
used. Salts of AD are typically described herein.
It is a crystal like Form 4.

Embodiments include compositions that transiently occur when a method step or operation is performed. For example, when the sodium alkoxide is contacted with a 9- (2-hydroxyethyl) adenine solution, the composition at the start of mixing will include a negligible amount of sodium alkoxide.
The composition is generally present as a heterogeneous mixture prior to sufficient agitation to mix the solutions. Such compositions usually contain negligible reaction products, and predominantly reactants. Similarly, as the reaction proceeds, the proportions of reactants, products, and by-products change relative to each other. These transient compositions are intermediates that emerge as the steps of the process are performed, and they are expressly included as an embodiment of the invention.

The present invention includes a mixture of two or more different crystal forms or forms, such as Form 1 and Form 2 crystals, Form 1, Form 2 and Form 4 crystals, or Form 2 and Form 4 crystals. Including the composition. A mixture of Form 1 and Form 2 AD crystals may be present in a pharmaceutical formulation or product thereof, and typically such mixture is at least about 70%, usually at least about 90%.
%, Including Form 1, but in some cases,
Up to about 70% of such mixtures may contain Form 2 and / or amorphous AD.

Crystal form of AD AD is as described (Starrett et al., J. Med. Chem. (1
994) 19: 1857-1864) prepared and recovered and recovered from a silica gel column in a solution of methanol (about 4%) and methylene chloride (about 96%) by rotary evaporation under reduced pressure at about 35 ° C. By doing so, it precipitates as an amorphous or amorphous solid.
Here, the inventors have discovered that AD can be prepared in crystalline form.

We have found several different crystalline A
Form D was identified. We characterized them by several methods, usually by XRD and DSC thermography. Researchers commonly use XRD to characterize or identify crystalline compositions (see, for example, US Pharmacopoea, 2nd.
Volume 3, 1995, Method 941, 1843-1845,
U. S. P. Pharmacopeal Conve
Ntion, Inc. , Rockville, MD;
Stout et al., X-ray Structure De
termination; A Practical G
guide, MacMillan Co. , New Yo
rk, N.N. Y. 1968). Diffraction patterns obtained from crystalline compounds are often diagnostic material for a given crystal form, but weak or very weak diffraction peaks appear to always appear in duplicated diffraction patterns obtained from successive batches of crystals. Not necessarily. This is especially the case when other crystalline forms are present in the sample in appreciable amounts, for example when the crystals of form 1 are partially hydrated into crystals of form 2. The relative intensities of the bands, especially at low-angle X-ray incidence angles (low 2θ), can be altered by suitable orientation effects resulting from differences in, for example, crystal habit, grain size, and other conditions of measurement. Therefore, the relative intensities of the diffraction peaks are not a definitive diagnostic of the crystal form in question. Instead, the relative positions of the AD crystals rather than their intensities should be examined to determine if they are one of the forms described herein. The individual XRD peaks in different samples are generally about 0.
It is located within the range of an angle 2θ of 3 to 1 degree. A broad XRD peak can consist of two or more individual peaks located closely together. For sharp isolated peaks, the peak is usually found in a continuous XRD analysis within an angle 2θ of about 0.1 degree. Given that the same instrument is used to measure the XRD spectra of compounds in successive XRD analyses, the differences in XRD peak placement are mainly due to differences in sample preparation or the purity of the samples themselves. When identifying a sharp isolated XRD peak at a given position as placed, eg, about 6.9, that peak is 6.9 ± 0.1.
Means to be in. When identifying a broad XRD peak for a given 2θ value at a given position as placed, this means that the peak is at that 2θ value ± 0.3.

Note that it is not necessary to rely on all the bands observed in the high purity AD reference sample herein; even a single band, eg Form 1
6.9 may be a diagnostic material for a given crystalline form of AD. The identification should focus on the location of the bands and the general pattern, especially the selection of unique bands for different crystalline forms.

Additional diagnostic techniques that can optionally be used to identify crystalline AD are differential scanning calorimetry (DSC), melting point determination, and infrared absorption spectroscopy (IR).
including. DSC measures the thermal transition temperature at which a crystal absorbs or releases heat as the crystal structure changes or it dissolves. Thermal transition temperatures and melting points are typically in the range of about 2 ° C, usually in the range of about 1 ° C by continuous analysis. The present inventors have confirmed that the compound has a DS
When describing as having a C peak or melting point, it is
Means the DSC peak or melting point is within ± 2 ° C. DSC provides an alternative means for distinguishing different AD crystalline forms. Different crystalline forms can be identified, at least in part, based on their different transition temperature profiles. IR measures the absorption of infrared light caused by the presence of certain chemical bonds in the molecule associated with groups that vibrate in response to light. Therefore, DSC and / or IR can provide physicochemical information that can be used to describe AD crystals.

(Form 1) Single crystal X-ray crystallography shows form 1
Was used to characterize the AD. 3.00 <2θ
324 measured at I> 10σ in <45.00 ° range
Lattice constant and orientation matrix obtained from a least-squares optimization using two reflection points.
n matrix) corresponded to a C-centered monoclinic lattice specified as follows: a = 12.85Å, b = 24.
50Å, c = 8.28Å, β = 100.2 °, Z = 4,
Space group Cc.

The XRD pattern for Form 1 is typically about 6.9.
Typically about 6.9 and about 20.7, or more typically about 6.9, about 15.7, and about 20.
7, and usually at least about 6.9, about 11.8,
Peaks are displayed at about 15.7 and about 20.7. Typically, an XRD peak of about 6.9, or usually (1) this peak plus one or two peaks, or (2) about 6.9 peak +
Either one or two other peaks combined with different differential scanning calorimetry data or melting point data are of the form 1
Is sufficient to distinguish the crystals of Form I from other forms, or to identify Form 1 itself. Form 1 spectra are generally about 6.9, about 11.8, about 12.7, about 15.
7, about 17.2, about 20.7, about 21.5, about 22.
It has peaks at 5 and about 23.3. Form 1 XR
The D pattern is typically about 6.9 and / or 11.8 and / or 15.7 and / or 17.2 and / or
Alternatively, the peak (s) is / are present at any one (or combination) of 20.7 and / or 23.3.
FIG. 1 shows an X-ray diffraction pattern of a representative Form 1 crystal. However, it should be understood that Figures 1-26 are merely exemplary, and that diagnostic depictions of other crystalline AD preparations may deviate from these figures.

Form 1 AD is anhydrous and contains little or no water. In general, Form 1 crystals usually contain less than about 1%, typically less than about 0.5%, and usually less than about 0.2% water. Furthermore, Form 1 crystals usually contain less than about 20%, typically less than about 10%, often less than about 1%, and usually less than about 0.1% amorphous AD. Often, Form 1 crystals do not contain amorphous AD that is detectable by DSC, XRD, or polarized light microscopy at 100x magnification. Form 1 AD is typically substantially free of crystallization solvent, ie, typically less than about 1% and usually less than about 0.6% when properly recovered from the crystallization bath. , And it is lattice-entr
ained) Does not contain solvent molecules.

Form 1 crystals are generally about 25-150 μm.
m, typically about 30-80 μm, with a median size due to light scattering. Individual form 1
Preparations usually have a length in the range of about 1 to 200 μm, and about 60 to 200 for individual crystals in the preparation.
Includes crystals with a typical maximum dimension of μm. In some Form 1 formulations, about 1-10% of the crystals in the formulation have a maximum dimension greater than 250 μm. Figure 4-
The Form 1 crystals shown at 10 typically have tablet, plate, needle and / or irregular crystal habits. Aggregation of Form 1 crystals also results in about 25-15
It occurs in a typical diameter range of 0 μm.

Form 1 crystals exhibit a DSC endothermic transition at about 102 ° C. (see FIG. 2) and an IR spectrum essentially as depicted in FIG. Different Form 1 crystalline preparations have bulk densities of about 0.15-0.60 g / mL, usually about 0.25-0.50 g / mL, about 0.1-0.50 g / mL.
0~2.20m ² / g, usually about 0.20~0.60m
^With a surface area of ² / g. Therefore, AD of form 1
Is about 6. at an angle 2θ using Cu-Kα irradiation.
XRD spectral peaks appearing on any one (or combination) of 9 and / or 11.8 and / or 15.7 and / or 20.7 and an endotherm as measured by differential scanning calorimetry at about 102 ° C. Characterized by metastases. Alternatively, Form 1 AD is Cu-Kα.
Using irradiation, 6.9 ± 0.1, 1 at angle 2θ
1.8 ± 0.1, 15.7 ± 0.1, 17.2 ± 0.
Clear XRD spectral peaks appearing at 1, 20.7 ± 0.1, and about 102.0 by differential scanning calorimetry.
It is characterized by an endothermic transition peak as measured at ± 2 ° C and / or an endothermic onset at 99.8 ± 2 ° C.

Form 2 A Form 2 XRD pattern (an example of which is depicted in FIG. 11) is typically about 22.0, typically about 18.3 and about 22.0, or more representative. Typically about 9.6, about 18.3 and about 22.0, and usually at least about 9.6, about 18.3, about 22.
Peaks (one or more) are shown at 0 and about 32.8. Typically any 3 or 4 of these 4 characteristic XRD peaks, or usually (1) 4
Peaks, or (2) either two or three of these peaks, combined with different scanning calorimetry data or melting point data, to distinguish Form 2 crystals from other forms, or Sufficient to identify Form 2 itself. Form 2 XRD patterns are typically about 8.7.
~ 8.9, about 9.6, about 16.3, about 18.3, about 1
8.9, about 19.7, about 21.0 to 21.3, about 21.
4, about 22.0, about 24.3, about 27.9, about 30.
8 and peaks at any one (or combination) of about 32.8.

Form 2 crystals are AD dihydrates, and they are generally essentially free of detectable crystallization solvents other than water. Form 2 crystals usually contain less than about 30%, typically less than about 10%, often less than about 1%, and usually less than about 0.1% amorphous AD. Generally, the crystals are D
Free of amorphous AD detectable by SC, XRD, or polarized light microscopy at 100 × magnification. Form 2 crystals typically have a median size of about 15-85 μm, usually about 25-80 μm, by light scattering. The individual Form 2 preparations usually contain crystals having a length in the range of about 1 to 300 μm. Form 2 crystals have a DSC endothermic transition at about 73 ° C. (see FIG. 12) and substantially FIG.
3 has an IR spectrum as shown in 3. Thus, Form 2 AD uses Cu-Kα irradiation to generate any one of about 9.6 and / or about 18.3 and / or about 22.0 and / or about 32.8 at an angle 2θ. XRD spectral peaks appearing (or in combination) and an endothermic transition as measured by differential scanning calorimetry at about 73 ° C. Alternatively, Form 2 AD is 9.6 ± 0.1, 18.3 ± 0.1, 22.0 ± 2 at an angle 2θ using Cu-Kα irradiation.
Clear XRD spectral peaks appearing at 0.1, 24.3 ± 0.1 and 32.8 ± 0.1, and endothermic transition peaks as measured by differential scanning calorimetry at about 72.7 ± 2 ° C. / Or characterized by an endotherm onset of 69.5 ± 2 ° C.

Form 3 An XRD pattern of Form 3, such as that shown in FIG. 14, is usually about 8.1, typically about 8.1 and about 25.4, or more typically. Peaks appear at about 8.1, about 19.4, and about 25.4. Typically these three characteristic XRDs
Any one or two of the peaks, or usually (1) three or four of these peaks, or (2) two of these peaks combined with different scanning calorimetry data or melting point data Alternatively, any of the three is sufficient to distinguish a Form 3 crystal from other forms or to identify Form 3 itself. Form 3 AD has an AD of about 8 as measured by differential scanning calorimetry.
It has an endothermic transition at 5 ° C (Figure 15). Form 3 spectra are typically about 8.1, about 8.7, about 14.1, about 16.
5, about 17.0, about 19.4, about 21.1, about 22.
6, about 23.4, about 24.2, about 25.4, and about 3
It has a peak at any one (or combination) of 0.9.

Unlike Forms 1 and 2, the Form 3 crystals contain about 1 equivalent of methanol in the crystal lattice. Methanol is typically provided by the crystallization solvent. However, Form 3 is essentially free of other detectable solvents or water. Form 3 crystals usually contain less than about 20%, typically less than about 10%, often less than about 1% and usually less than about 0.1% amorphous AD. The crystal is DSC,
It does not contain amorphous AD detectable by XRD or by polarization microscopy at 100 × magnification. Form 3 crystals are typically about 20-150 μm, usually about 3 by light scattering.
It has a median size of 0 to 120 μm. Individual form 3
The preparation usually comprises crystals having a length in the range of about 1 to 300 μm.

Form 4 An XRD pattern of Form 4, such as that shown in FIG. 16, is typically about 26.3,
Typically about 26.3 and about 31.7, or typically about 26.3, about 31.7, and about 15.2.
Or it usually shows peaks at about 26.3, about 31.7, about 15.2, and about 21.0. Typically these 4
One of the characteristic XRD peaks, or usually (1) three of these peaks, or (2) two or three of these peaks combined with different differential scanning calorimetry data or melting point data. Is sufficient to distinguish Form 4 crystals from other forms, or to identify Form 4 itself. Form 4 AD is about 121 ° C. and about 148 as measured by differential scanning calorimetry.
It has an endothermic transition at ° C (Fig. 17). Form 4 spectra are typically about 9.8, about 15.2, about 15.7, about 18.
1, about 18.3, about 21.0, about 26.3, about 31.7
Has a peak in any one (or combination) of. Therefore, Form 4 AD uses Cu-Kα irradiation to
XRD spectral peaks appearing at any one (or combination) of about 15.2 and / or about 21.0 and / or about 26.3 and / or about 31.7 at θ and about 121 by differential scanning calorimetry. It is characterized by an endothermic transition as measured at 0.3 ° C and about 148.4 ° C. Alternatively, Form 4 AD is Cu-Kα
Using irradiation, 9.8 ± 0.1, 1 at angle 2θ
8.1 ± 0.1, 21.0 ± 0.1, 26.3 ± 0.1
And apparent XRD spectrum peaks appearing at 31.7 ± 0.1 and about 121. by differential scanning calorimetry.
Characterized by endothermic transition peaks as measured at 3 ± 2 ° C and 148.4 ± 2 ° C.

(Crystalline salts of organic and inorganic acids) FIGS.
26 shows an XRD spectrum obtained from a crystalline salt of AD and an organic or inorganic acid, or alternatively a complex thereof.
These salts include hemisulfate or complex (FIG. 18), hydrobromide or complex (FIG. 19), nitrate or complex (FIG. 20), mesylate (CH ₃ SO ₃ H) salt or complex. (FIG. 21), ethyl sulfonate (C ₂ H ₅ SO
₃ H) or complex (FIG. 22), β-naphthylene sulfonate or complex (FIG. 23), α-naphthylene sulfonate or complex (FIG. 24), (S) -camphor sulfonate or Complex (FIG. 25) and succinate or complex (FIG. 26). These XRD spectra show a number of peaks that characterize the compounds and distinguish each compound from other crystalline forms.

FIG. 18 shows that the hemisulfate or complex has about 8.0, about 9.5, about 12.0, about 1 at angle 2θ.
4.6, about 16.4, about 17.0, about 17.5 to 17.
7, about 18.3, about 19.0, about 20.2, about 22.
Any one (or combination) of 7, about 24.1, and about 28.2 is shown to have a unique XRD peak. The salt or complex has a melting point of about 131-134 ° C. Therefore, the salt or complex may be associated with these unique XR
The four D peaks are about 12.0, about 14.6, about 16.4,
And about 17.5 to 17.7. The compound further has 3 or 4 of these XRD peaks and is about 131-134 ° C.
Can be characterized as having a melting point of. Alternatively, the AD hemisulfate is prepared using Cu-Kα irradiation,
8.0 ± 0.1, 12.0 ± 0.1, 1 at angle 2θ
4.6 ± 0.1, 16.4 ± 0.1, and 17.5
It is characterized by a clear XRD spectral peak appearing at 17.7 ± 0.3 and a melting point of 131-134 ± 2 ° C.

FIG. 19 shows that the hydrobromide salt or complex was
At angle 2θ, about 13.2, about 14.3, about 15.
9, about 17.8, about 20.7, about 21.8, about 27.
2, and any one (or combination) of about 28.1
Shows that it has a unique XRD peak. The salt or complex decomposes on heating at about 196-199 ° C.
Thus, the salt or complex has four unique XRD peaks at about 13.2, about 14.3, about 17.8, and about 2.
It is characterized as having in 8.1. The compound further has 3 or 4 of these XRD peaks and is characterized as decomposing at about 196-199 ° C when heated. Alternatively, the hydrobromide of AD is 1 at an angle 2θ using Cu-Kα irradiation.
3.2 ± 0.1, 14.3 ± 0.1, 17.8 ± 0.
Clear XRD spectral peaks appearing at 1, 20.7 ± 0.1, and 27.2 ± 0.1, and 196-1
It is characterized by a decomposition point of 99 ± 2.0 ° C.

FIG. 20 shows that the nitrate or the composite has an angle 2θ.
, About 8.0, about 9.7, about 14.1, about 15.
2, about 16.7, about 17.1, about 18.3, about 18.
9, about 19.4, about 20.0, about 21.2, about 22.
3, about 23.2, about 24.9, about 27.6, about 28.
It is shown that any one (or combination) of 2, about 29.4, and about 32.6 has a unique XRD peak. The salt or complex, when heated, is about 135 to 13
Decomposes at 6 ° C. Therefore, this salt or complex has four unique XRD peaks of about 14.1, about 23.2, about 2.
9.4, and about 32.6. The compound may be further characterized as having 3 or 4 of these XRD peaks and having a melting point of about 131-134 ° C. Alternatively,
Nitrate of AD was 8.0 ± 0.1, 14.1 ± 0.1, 23.2 ± at angle 2θ using Cu-Kα irradiation.
Clear XRD spectral peaks appearing at 0.1, 29.4 ± 0.1, and 32.6 ± 0.1, and 135
Characterized by a decomposition point of ˜136 ± 2 ° C.

FIG. 21 shows that the mesylate salt or complex is
At an angle 2θ, about 4.8, about 15.5, about 16.2,
It is shown that any one (or combination) of about 17.5, about 18.5, about 20.2, about 24.8, about 25.4, and about 29.5 has a unique XRD peak. . This salt or complex has a melting point of about 138-139 ° C. Therefore, this salt or complex contains four unique XR
It is characterized as having a D peak at about 4.8, about 15.5, about 20.2, and about 24.8. The compound further comprises 3 or 4 of these XRD peaks.
Individual and can have a melting point of about 138-139 ° C. Alternatively, the mesylate of AD is 4. at angle 2θ using Cu-Kα irradiation.
8 ± 0.1, 15.5 ± 0.1, 16.2 ± 0.1, 2
Clear XRD spectral peaks appearing at 0.2 ± 0.1, and 24.8 ± 0.1, and 138-139 ±
It is characterized by a melting point of 2 ° C.

FIG. 22 shows that the ethyl sulfonate or the complex is about 4.4, about 8.8, about 18.
8, about 23.0 to 23.3, and about any of 27.3 are shown to have a unique XRD peak. This salt or complex is about 132-133.
It has a melting point of ° C. Therefore, the salt or complex is 4
About 4.4, about 8.8, about 1 unique XRD peaks
8.8, and about 27.3. The compound may be further characterized as having 3 or 4 of these XRD peaks and having a melting point of about 132-133 ° C. Alternatively,
The ethyl sulfonate of AD was 4.4 ± 0.1, 8.8 ± 0.1 at an angle 2θ using Cu-Kα irradiation.
It is characterized by apparent XRD spectral peaks appearing at 18.8 ± 0.1, 23.0 to 23.3 ± 0.3, and 27.3 ± 0.1, and a melting point of 132 to 133 ± 2 ° C.

FIG. 23 shows that the β-naphthylene sulfonate or the complex has about 9.8, about 13.
1, about 16.3, about 17.4, about 19.6, about 21.6
Any one (or combination) of ~ 22.3, about 23.4, about 24.1-24.5, and about 26.6 is shown to have a unique XRD peak. This salt or complex has a melting point of about 156-157 ° C. Therefore, this salt or complex has four unique XRD peaks of about 1
3.1, about 17.4, about 23.4, and about 26.2. The compound may be further characterized as having three or four of these XRD peaks and having a melting point of about 156-157 ° C. Alternatively, the β-naphthylene sulfonate of AD was 9.8 ± 0.1, 13.1 ± 0.1, 17.4 ± 0.
Clear XRD spectral peaks appearing at 1, 23.4 ± 0.1, and 26.2 ± 0.1, and 156-1
It is characterized by a melting point of 57 ± 2 ° C.

FIG. 24 shows that the α-naphthylene sulfonate or the complex is about 8.3, about 9.8 at an angle 2θ.
About 11.5, about 15.6, about 16.3, about 16.7 to 1
7.4, about 19.6, about 21.0, about 22.9, about 2
It is shown to have a unique XRD peak at any one (or combination) of 3.7, about 25.0, and about 26.1. The salt or complex has a melting point of about 122-128 ° C. Therefore, this salt or complex has four unique XRD peaks at about 9.8, about 15.6, about 19.
6, and about 26.1. The compound further has 3 of these XRD peaks.
Can be characterized as having one or four and having a melting point of about 122-128 ° C. Or AD
Α-naphthylenesulfonate of 9.8 ± 0.1, 15.6 ± 1 at an angle 2θ using Cu-Kα irradiation.
It is characterized by distinct XRD spectral peaks appearing at 0.1, 19.6 ± 0.1, 21.0 ± 0.1, and 26.1 ± 0.1, and a melting point of 122-128 ± 2 ° C.

FIG. 25 shows that the (S) -camphor sulfonate or complex is about 5.4, about 6.
5, about 13.7, about 15.5, about 16.8 to 17.2,
About 19.6, about 20.4 to 20.7, about 21.2, about 2
3.1, about 26.1, about 27.5, about 28.4, about 3
1.3, and any one (or combination) of about 32.2 is shown to have a unique XRD peak. This salt or complex has a melting point of about 160-161 ° C. Therefore, this salt or complex contains four unique XR
Characterized as having a D peak at about 5.4, about 6.5, about 13.7, and about 16.8-17.2. The compound further has 3 of these XRD peaks.
Or 4 and can be characterized as having a melting point of about 160-161 ° C. Or AD
(S) -camphorsulfonate of 5.4 ± 0.1, 6.5 ± at angle 2θ using Cu-Kα irradiation.
0.1, 13.7 ± 0.1, 16.8 to 17.2 ± 0.
3, and a distinct XRD spectral peak appearing at 19.6 ± 0.1 and a melting point of 160-161 ± 2 ° C.

FIG. 26 shows that the succinate or complex has about 4.7, about 9.5, about 10.6, about 1 at angle 2θ.
4.9, about 16.3, about 17.4, about 17.9, about 1
9.9, about 20.8, about 22.1, about 23.9-24.
It is shown that any one (or combination) of 2, about 26.5, about 27.6, and about 28.2 has a unique XRD peak. This salt or complex is about 122-12
It has a melting point of 4 ° C. Therefore, the salt or complex is
4 unique XRD peaks at about 4.7, about 9.5, about 1
4.9, and about 17.4. The compound may be further characterized as having 3 or 4 of these XRD peaks and having a melting point of about 122-124 ° C. Alternatively,
AD succinate uses Cu-Kα radiation to
at θ of 9.5 ± 0.1, 14.9 ± 0.1, 16.
3 ± 0.1, 17.4 ± 0.1, and 23.9-2
It is characterized by a clear XRD spectral peak appearing at 4.2 ± 0.3 and a melting point of 122-124 ± 2 ° C.

Embodiments of the present invention include compositions comprising a crystalline salt of adefovir dipivoxil (eg, a salt as characterized above) and a pharmaceutically acceptable excipient (s). . Other embodiments are pharmaceutically acceptable by contacting a crystalline salt of adefovir dipivoxil (eg, a salt as characterized above) and a pharmaceutically acceptable excipient (s). A process for preparing the various compositions. Another embodiment is
Included are crystalline salts of adefovir dipivoxil (eg, salts as characterized above) and products produced by the process of contacting a pharmaceutically acceptable excipient (s).

(Method for synthesizing AD) Illustration A below
Shows a working flow diagram of an exemplary process for making AD and Form 1 AD crystals.

[0108]

[Chemical 1] The steps of the process shown in Diagram A and the following description are:
It can be scaled up or down if desired.

(Synthesis Method of Diethyl p-Toluenesulfonyloxymethylphosphonate) In an embodiment, the synthesis of diethyl p-toluenesulfonyloxymethylphosphonate shown in Scheme A, Step 1 is described as follows. Diethyl phosphite (0.8 kg), paraformaldehyde (0.22 k) in toluene (2.69 kg) in a reaction vessel with an inert atmosphere (eg nitrogen).
g), and a mixture of triethylamine (0.06 kg) are heated to 87 ° C. (84-110 ° C.) for 2 hours with stirring, then to reflux, and left to reflux for 1 hour until the reaction is complete. To do. The completion of the reaction
Monitored by TLC (trace or no detectable diethyl phosphite) and ¹ H NMR
Is confirmed by showing a peak of diethyl phosphite of only 1% at δ 8.4 to 8.6 ppm. The solution was cooled to about 1 ° C (-2 to 4 ° C) and p-toluenesulfonyl chloride (1.0 kg) was added, then 10 ° C.
Triethylamine (0.82 kg) is added slowly (exothermic reaction over about 3-6 hours) at a temperature of no more than. The resulting mixture is warmed to 22 ° C (19-25 ° C) and stirred for at least 5 hours (typically about 16-24 hours) until the reaction is complete. Reaction completion was monitored by TLC (trace or no detectable p-toluenesulfonyl chloride),
And confirmed by ¹ H NMR (δ 7.9 ppm
P-toluenesulphonyl chloride doublet is no longer detected). Solids are removed by filtration and washed with toluene (0.34 kg). The combined washings and filtrates were washed twice with water (1.15 kg each) or, if necessary, water (1.15 kg), 5% aqueous sodium carbonate solution (3.38 kg), and twice with water ( 1.15 kg each)
Wash in any of the order. If an emulsion forms, brine may be added to the original organic / water mixture. The organic phase, which is only 50 ° C., is distilled under reduced pressure (only 10% relative to LOD and the water content is KF (Karl Fisc).
her) titrating to only 0.5%) to give the title compound as an oil with a purity of about 85-95%, excluding toluene. The oil can become viscous on cooling.

(Synthesis Method of 9- (2-Hydroxyethyl) Adenine) In an embodiment, the synthesis of 9- (2-hydroxyethyl) adenine shown in Scheme A, Step 2 is described as follows. In a reaction vessel having an inert atmosphere (eg nitrogen), add sodium hydroxide (6 g) in DM
Adenine (1.0 kg) and molten ethylene carbonate (0.72 kg, melting point 37-39 in F (2.5 kg))
C.) and the mixture is heated to 125.degree. C. (95.degree. C. to reflux) with stirring until the reaction is complete (about 3-9 hours when the temperature of the mixture is 110.degree. C. to reflux, or 95-. It is about 15 to 48 hours at 110 ° C).
Reaction completion is monitored by HPLC (0.5
Only a percentage of adenine remains). The mixture is cooled to below 50 ° C. and diluted with toluene (3.2 kg). Cool the resulting slurry to 3 ° C (0-6 ° C),
Then stir for at least 2 hours. Filter the slurry,
The filter cake is then chilled (0-5 ° C) with toluene 2
Wash once (0.6 kg each). Filter cake under reduced pressure 3
Dry at 5-70 ° C (by ¹ H NMR or LOD
Triturate only 2%), and trituration if necessary to give the title compound as a white to whitish powdery solid.

(Synthesis Method of 9- [2- (Diethylphosphonomethoxy) ethyl] adenine) This compound was treated with sodium alkoxide (C1-6 alkyl), and 9-
Prepared using a composition containing (2-hydroxyethyl) adenine. Sodium alkoxide, typically sodium t-butoxide or sodium i-propoxide, was treated with 9- (2-hydroxyethyl) in a solvent such as DMF at a temperature of about 20-30 ° C. for about 1-4 hours. Contact with adenine. The synthesis typically gives good results with 1 molar equivalent of 9- (2-hydroxyethyl) adenine and about 1.2 to 2.2 molar equivalents of sodium alkoxide.

In an embodiment, shown in Scheme A, step 3.
9- [2- (diethylphosphonomethoxy) ethyl]
The synthesis of adenine is described as follows. Inert atmosphere
In a reaction vessel containing gas (for example, nitrogen), 9- (2-hi
Droxyethyl) adenine (1.0 kg) and DMF
(4.79 kg) of slurry for about 30-60 minutes for about 130
Warm up to ° C (125-135 ° C). Contents of reaction vessel
Stir vigorous stirring to approximately 25 ° C (20-30 ° C).
Cool rapidly with and stir vigorously and adjust the contents temperature.
While maintaining at 25 ° C (20-30 ° C), sodium t
ert-butoxide (0.939 kg) for about 1 to 3 hours
Add it in small portions. All sodium tert
-After adding butoxide, stir for about 15-45 minutes.
Maintain agitation and temperature. Then, the content of the reaction vessel is reduced to about −
Cool to 10 ° C (-13 to 0 ° C) and p-tolue
Diethylsulfonyloxymethyl-phosphonate (purity
2.25 kg) of DMF (1.22 kg)
The solution is added over about 5-10 hours. The reaction mixture
Until completed (typically p-toluenesulfonyl
Add the last part of diethyl xymethyl-phosphonate
Approximately 0.5 to 2 hours after it has stopped, about -5 ° C (-10 to 0)
C)). Reaction completion is monitored by HPLC.
(Only 3% of 9- (2-hydroxyethyl) a)
Denin remains). Glacial acetic acid (0.67 kg) in a container
Controllable addition of temperature to only 20 ° C. about
Stir the mixture at 22 ° C (15-25 ° C) for about 15-45 minutes.
Stir. Vacuum the quenched mixture until distillation stops.
Concentrate below and then cool the contents to below 40 ° C. salt
Methylene chloride (16.0 kg) was added and 20 ° C. (1
Stir the contents at 5-25 ° C) for at least 1 hour. D
MF content vs. total solids (NaOTs (sodium
), NaOAc, Et_TwoPMEA) is more than 20%
large(¹(By 1 H NMR), the mixture is distilled
Concentrate under reduced pressure until stopping and cool the contents to below 40 ° C
Methylene chloride (16 kg) and about 20 ° C.
(15-25 ° C) at least 1 hour for reaction vessel contents
Stir. Add diatomaceous earth (0.5 kg) and contents
(This is at about 20 ° C (15-25 ° C))
Also stir for 1 hour. Solids are removed by filtration and C
H_TwoCl _TwoWash 3 times (about 1 kg each). To 80 ° C
Concentrate not too much filtrate and washing solution under reduced pressure until distillation stops
Cool the contents of the reaction vessel to below 40 ° C and
Add Tiren (5.0 kg) to the residue and about 25 ° C
Stir the contents at (20-40 ° C.) to dissolve the solid.
Depressurize the resulting solution, which is no more than 80 ° C, until distillation stops.
Concentrate below. Add methylene chloride (7.0 kg) and add
Stir the contents at about 25 ° C (20-40 ° C) to remove solids.
Dissolve. DMF content to diethyl PMEA is 1
If greater than 2%, depressurize the mixture at only 80 ° C
Concentrate underneath and cool the contents to below 40 ° C.
(7.0 kg) and about 25 ° C (20-40
Stir the contents at (° C.) to dissolve the solid. About the mixture
Stir at 25 ° C (22-30 ° C) for about 15-45 minutes
It is washed with water (0.8 kg). Phase separation in 4 hours
And then the phases are separated. The aqueous phase, the solution at about 25 ℃
While maintaining at (22-30 ° C), methylene chloride (once
(1.5 kg per wash) for about 15-45 minutes
By back-extracting twice, followed by at least 2 hours for phase
To separate. Then the combined organics at only 80 ° C
The phases are concentrated under reduced pressure until the distillation has stopped. Toluene (3.0
kg), and at about 25 ° C (22-30 ° C) about 15-4
The resulting mixture is stirred for 5 minutes and is no more than 80 ° C.
Is azeotropically distilled under reduced pressure. Add toluene (3.0 kg),
And heat the mixture to about 80 ° C (75-85 ° C),
Stir for about 15 to 45 minutes, 30 ° C for about 60 to 90 minutes
Cool to below, then cool to about 0 ° C (-3 to 6 ° C)
To do. At least 12 with gentle stirring at about 0 ° C
After a time, the resulting slurry is filtered and the filter
The cake is washed with cold (about 0-6 ° C) toluene three times (one wash).
0.2 kg per) wash. Approximately 50 moist cake under reduced pressure
C. (35-65.degree. C.) and dried product
Smash. Monitor product drying for water removal
Yes (KF titration detected only 0.3% water
). An inert atmosphere is maintained throughout step 3.

(Method for Synthesizing PMEA) In one embodiment, the synthesis of PMEA shown in Scheme A, Step 4, is described as follows. Diethyl PMEA (1.00k) in a reaction vessel with an inert atmosphere (eg, nitrogen).
A mixture of g), acetonitrile (2.00 kg), and bromotrimethylsilane (1.63 kg) is heated to reflux with stirring and maintained at reflux for about 1-3 hours until the reaction is complete. Completing the reaction is completed by ^{3 1} P
Monitor by NMR or HPLC (diethyl P
No MEA detected and less than 2% monoethyl PM
EA is detected). The solution below 80 ° C is distilled under reduced pressure to a semi-solid, which is taken up in water (2.00 kg) and stirred for about 30-60 minutes at about 55 ° C (52-5 ° C).
Warm to 8 ° C.) to dissolve all solids. The resulting mixture is cooled to about 22 ° C (19-25 ° C), adjusted to pH 3.2 with aqueous sodium hydroxide and the contents are about 75 ° C until the consistency becomes thin (about 15-120 minutes). (72-7
Heat to 8 ° C), cool to about 3 ° C (0-6 ° C), and stir for at least 3 hours (3-6 hours). Filter the slurry and filter the cake with water (1.00 kg).
Wash with. The wet cake is suspended in water (3.75 kg) and the suspension is stirred vigorously at about 75 ° C (72%).
~ 78 ° C). After stirring for about 2 hours, the slurry is cooled to about 3 ° C (0-6 ° C) and at least an additional 2
Stir for hours. The slurry is filtered and the filter cake is washed with 2 parts of water (0.50 kg per wash) and 2 parts of acetone (1.00 kg per wash).
Wash continuously with. The isolated solid is dried in vacuo at about 90 ° C. or lower to a low water content (KF titration detects less than 0.5% water) to provide PMEA as white crystals. The product is ground to a fine particle size.

Synthetic Method for AD An exemplary method for preparing AD is to suspend 1 molar equivalent of PMEA in about 5.68 to 56.8 equivalents of NMP / equivalent PMEA, and the PMEA. After suspension, about 2 to 5 molar equivalents, often about 2.5 to 3.5, usually about 3 molar equivalents of triethylamine ("TEA") are added to the solution with gentle or moderate agitation. including. Then about 3-6 molar equivalents, often about 4.5-5.5 molar equivalents, usually about 5 equivalents of chloromethyl pivalate are added to give a reaction mixture. We usually prepare the reaction mixture at room temperature. The reaction mixture is heated to below 66 ° C, typically about 28-
The temperature is maintained at 65 ° C, usually between about 55 and 65 ° C for about 2 to 4 hours to allow the reaction to proceed. The reaction mixture is about 28-6
The time required to heat to 5 ° C is not important,
And can vary depending on the volume of the reaction mixture and the capabilities of the equipment used to heat the mixture. Gentle or moderate agitation keeps the solids in suspension throughout the reaction, and this minimizes large splashes of reactants in the reaction vessel. This method typically results in a product comprising AD produced by the reaction process of the listed reactants under defined conditions.

In one embodiment, Scheme A, step 5
The conversion of PMEA to AD shown in Figure 1 is described as follows. In a reaction vessel having an inert atmosphere (eg, nitrogen), 1-methyl-2-pyrrolidinone (3.15k
g), PMEA (1.00 kg), triethylamine (1.11 kg), and chloromethyl pivalate (2.76 kg) were heated to about 60 ± 3 ° C (66 ° C or less) and moderately stirred. Use, ³¹ P
4 until the reaction is complete, as indicated by NMR or HPLC (15% or less mono (POM) PMEA)
Stir for no more than 1 hour (1-4 hours). The mixture is diluted with isopropyl acetate (12.00 kg), cooled to 25 ± 3 ° C. and stirred for about 30 minutes. Solids are removed by filtration and washed with isopropyl acetate (5.0 kg). Combine the organics with water (3.70 kg per wash).
At 25 ± 3 ° C. for 15-45 minutes with medium agitation of the mixture. Combine the aqueous washes with isopropyl acetate (4.00 k per extraction).
g) twice, at a mixture temperature of 25 ± 3 ° C., about 15-45
Back-extract by stirring for minutes. Wash the combined organics at 25 ± 3 ° C. by stirring with water (1.80 kg) for 15-45 minutes, then concentrate the organics at about 35 ± 5 ° C. (40 ° C. or less) under reduced pressure to the original volume. Almost 40%
To Polishing Fi
(1 μm filter), and 1.
After a previous wash with 5 kg of isopropyl acetate, vacuum concentration of the organics is resumed until the pale oil remains as organics at about 35 ± 5 ° C (up to 50 ° C). Oils typically contain about 6-45% AD, usually about 30-42% AD.

Method for AD Crystallization Crystallization of AD from organic oils is usually accomplished by the following:
(1) PME existing as a reactant during AD synthesis reaction
Using a relatively small volume of NMP relative to the amount of A, ie less than about 10 mL NMP per gram of PMEA, and / or (2) sufficient time for vacuum distillation, usually at least about 4 By minimizing the amount of isopropyl acetate that remains entrained in the organic oil after vacuum distillation by allowing ~ 6 hours. Reaction starting material, eg N
Aggregates of MP or PMEA in oil can be described as about 2-20% of the crystallization solvent, but generally about 1-2.
%. About 2 if crystals are prepared from organic oils
0-45%, often about 30-42%, and usually about 35-42% AD is present in the oil prior to adding the crystallization solvent.

If desired, AD is crystallized from a supersaturated solution. Crystal nucleation occurs in such supersaturated solutions and readily leads to crystal formation. The rate of crystal nucleation typically increases with increasing degree of supersaturation and temperature. Supersaturated solutions are typically prepared by changing the temperature (usually by lowering it), evaporating the solvent, or altering the composition of the solvent (eg, by adding a miscible nonsolvent or antisolvent). A combination of these methods (eg, using evaporation under reduced pressure to also cool the solution while increasing the solute concentration) is also
Generate a supersaturated AD solution.

Crystalline AD is usually at least about 6%.
Of AD in a crystallization mixture, typically containing at least about 30%, usually at least about 35% AD, by forming crystals in the AD composition. Usually, crystallization is about 6-45% AD and about 5
It is carried out by preparing an AD solution containing 5-94% crystallization solvent. The upper limit of solubility of AD is about 10-41% at room temperature for most crystallization solvents. AD is unconditionally insoluble in some crystallization solvents (eg, the solubility of AD in di-n-butyl ether is less than about 0.3 mg / mL), and these solvents are used in AD solutions. Addition to the solution increases the degree of saturation or supersaturation of the solution. Usually, an organic solution containing an amount of AD near the upper limit of solubility in a crystallization solvent is used. The lower amount (about 6%) is the minimum amount of AD required in the solution to reliably obtain crystals. Certain solvents, such as methanol or CH ₂ Cl ₂ , can contain more than about 50% AD.

The temperature at which crystallization is carried out is not critical, and can be varied, as the crystallization process normally proceeds spontaneously over a range of temperatures. About 35 ℃, especially about 45
Crystallization at temperatures above ~ 50 ° C can result in reduced yields and / or increased impurities associated with crystallization. Crystallization generally is from about -5 ° C to about 50 ° C, often about 0-35 ° C.
C., usually in the temperature range of about 4-23.degree. If desired, crystallization temperatures below about -5 ° C can be used to increase the yield of crystals or to accelerate the rate of crystal formation, but low temperature processes can lead to increased by-products. . Therefore, almost ambient temperature (about 15-23 ℃)
It is generally more convenient and economical to use the solvent either at or at a typical cooling temperature (about 0-4 ° C.) that most cooling devices or methods can easily reach. The solution has a relatively low concentration, ie about 10-2
With 0% AD, crystallization at relatively low temperatures, i.e. about 0-15 <0> C, often improves the yield of crystals.

AD and crystallization solvent (s)
Heating the solution containing H.sub.2 to above room temperature, preferably to about 35.degree. C. appears to promote crystallization, presumably by increasing the rate of crystal nucleation. The time to heat the crystallization mixture to about 35 ° C is not critical and can vary depending on the capabilities of the equipment used, and usually ranges from about 20 to 45 minutes. The heating is then discontinued and the temperature is lowered by cooling or by lowering the temperature for about 10-120 minutes. During this time, crystals form and continue to form for at least about 4-36 hours. Crystallization usually begins immediately or shortly after the crystallization mixture reaches 35 ° C. The inventor performs crystallization by lowering the temperature to about 0-23 ° C after the solution reaches 35 ° C. Crystallization, with or without mild to moderate agitation, typically with mild agitation, gives conventionally good results.

Visible crystallization usually takes about 5 minutes to
It occurs over a period of about 72 hours and about 10-16 hours gives conventionally good results regardless of the solvent used. The time of crystallization is not critical and can vary, but relatively short crystallization times (about 30-90 minutes) can result in reduced recovery of AD. When a crystallization solvent is added to a reaction mixture containing another organic solvent (eg NMP), crystallization usually begins immediately once the temperature reaches about 35 ° C. or below and the solution becomes cloudy. become.

Crystallization is carried out in conventional laboratory or manufacturing plant equipment (eg, round bottom flasks, Erlenmeyer flasks, stainless steel reaction vessels, or glass lined reaction vessels). Crystallization is typically carried out using standard laboratory or commercial scale manufacturing equipment for mechanical agitation and temperature control.

When using a crystallization system containing two different solvents, the most polar solvent is generally added to the AD first, followed by the less polar solvent. If desired, after adding the first crystallization solvent, undissolved components, if any, are removed from the solution, for example by filtration or centrifugation. For example, to prepare Form 1 crystals from an organic solution containing AD and components from the AD synthesis reaction,
If acetone and di-n-butyl ether are used, usually acetone is added first. Similarly, n-butanol was added before adding the di-n-butyl ether,
Alternatively, ethyl acetate is added before the di-n-propyl ether. The solution containing the first polar solvent can be cloudy due to the precipitation of mono (POM) PMEA that may be present. The mono (POM) PMEA can then be removed from the solution by standard physical methods (eg filtration or centrifugation), followed by the addition of a second solvent (eg di-n-butyl ether).

The crystallization solvent used by the inventor to prepare Form 1 crystals generally contains less than about 0.2% water. A significant amount (ie about 1-2) in the crystallization solvent.
%) Water is present, the crystallization process produces various amounts of Form 2 crystals, which are also recovered with Form 1 crystals. The amount of water present during the crystallization reaction is optionally reduced by conventional means, which involves using anhydrous reagents or drying the solvent using molecular sieves or other known desiccants. Including those by doing. If desired, the amount of water that may be present in the AD containing organic solvent (eg, from the AD synthesis reaction containing the by-products and solvent as described above, such as the organic oils) will reduce the crystallization solvent. Before addition, it is reduced by using azeotrope with a co-solvent such as isopropyl acetate to reduce water.

In an embodiment, the crystallization of Form 1 AD shown in Scheme A, Step 6, is described as follows. A pale oil containing AD as described above was added to 3
Heat to 5 ± 3 ° C., dissolve in acetone (1.0 kg), and maintain the temperature at about 32-38 ° C. and with moderate stirring, di-n-butyl ether (5.00 k).
Dilute about 4 times with g). The clear solution was cooled to about 25-30 ° C. over about 30-60 minutes (90 minutes or less), seeded with a small amount of Form 1 AD crystals (about 5 g), then the contents were moderately stirred. Allow to cool to 22 ± 3 ° C. for about 30-60 minutes (90 minutes or less). Medium stirring of the mixture is continued at 22 ± 3 ° C. for a minimum of about 15 hours. The resulting slurry was filtered and the filter cake was washed with premixed acetone (0.27 kg) di-n.
-Butyl ether (2.4 kg) solution (1: 9 v / v)
Wash with. If necessary, pre-mixed acetone (0.57 kg) and di-n-butyl ether (4.92 kg) were added to the damp solid and the temperature of the contents was adjusted to 22 ± 3 ° C. for about 15 to 24 hours with stirring. Further purification by holding at The solids are then filtered and the filter cake washed with premixed acetone (0.27 kg) and di-n-butyl ether (2.4 kg). 35
The filter cake kept below ℃ (about 25 to 35 ℃) is dried under reduced pressure for about 1 to 3 days (LO below 0.5%).
D), Form 1 AD is obtained as a white to off-white powdery solid. Crush the dried product.

The present invention includes a method of preparing Form 2 crystals. While hydrates may be obtained by crystallization of AD from a crystallization solvent that contains water in an amount that does not interfere with crystallization, but provides water that is essential for hydration, Form 2 crystals give Form 1 crystals. It is conveniently prepared by hydration. Water can be present as ice, liquid water, or steam. Typically, it is placed in physical contact with Form 1 crystals under the conditions for the formation of Form 2 crystals. The Form 1 crystals are optionally in a gas (eg, air, at a relative humidity of at least about 75% to obtain complete conversion of Form 1 to Form 2 crystals.
Carbon dioxide, or nitrogen) is contacted with steam. Form 1 crystals are usually treated with air at about 18-30 ° C for about 1-10 days, or typically at room temperature and at a relative humidity of at least about 75% to obtain complete conversion to Form 2. Contacted. However, Form 1 crystals are essentially non-hygroscopic at room temperature in air at 54% relative humidity and do not increase water content after 13 days of exposure.

The process of hydration from Form 1 to Form 2 crystals produces a composition comprising a mixture of Form 1 and Form 2 AD crystals, wherein the proportion of Form 1 AD crystals is that of Form 2. Balanced with a certain AD, about 100% to 0%
Change. Therefore, the percentage of Form 2 crystals increases from 0% to 100% during the conversion process. These compositions may include formulations such as tablets.

As noted above, Form 2 crystals also have AD crystallization (otherwise in the presence of water, eg, about 2-5% water in the crystallization solvent (s)). Are used to make Form 1 crystals). Crystallization occurs essentially as described above for Form 1 crystals, eg, at about 0-23 ° C. for about 4-36 hours. Such a preparation is
Any Form 1 crystals may be included, but any remaining Form 1 crystals are optionally further exposed to water vapor as described above, or further to a crystallization solvent. It is converted to Form 2 crystals by adding water.

Normally, Form 3 crystals are prepared by growing the crystals in a solution of AD in anhydrous methanol.
Sufficient amorphous or crystalline AD is obtained by mixing at room temperature for about 10-15 minutes to obtain AD in methanol, or at least about as necessary to dissolve solid AD to obtain a solution. 100-150 mg AD / m
L methanol is used. The solubility of AD in methanol at room temperature is greater than 600 mg / mL. Crystallization then proceeds for about 4 to about 48 hours at a temperature of about -5 ° C to about 25 ° C, usually at a temperature of about 0-23 ° C.

The crystals obtained using isopropyl acetate as the sole crystallization solvent are typically predominantly columnar, which can be quite long, ie about 5%.
Measured to a length of 00 μm, there are also a few needles. FIG. 8 shows about 20-500 μm obtained by crystallization at a temperature higher than about 15 ° C. in isopropyl acetate.
Shows a columnar crystal with a length of.

Crystallization from a supersaturated AD solution and from a saturated or somewhat unsaturated AD solution was carried out as required by A
It is promoted or enhanced by adding seed crystals of D to the solution, but seed crystals are not required. For example, by adding a small amount of crystalline Form 1 AD to an organic solution as described above, such as an organic oil to which a crystallization solvent has been added, but not heated to 35 ° C., AD crystals are obtained. Seed crystals promote the formation of Form 1 crystals. Form 2 and Form 3 crystals are likewise suitable solutions (eg, an organic solution containing ethyl acetate and about 2% water for Form 2 crystals, or a saturated solution of AD in anhydrous methanol for Form 3 crystals). Can be obtained by seeding with the respective crystal form. The amount of crystals used as seed crystals is varied, if necessary, for optimum results. Generally, from about 0.1 to 1 L of AD recrystallization solution.
01.0 g of crystals are sufficient.

If desired, crystalline AD can be prepared as desired.
For example, it can be recrystallized to increase the purity of the crystals.

For example, Form 1 AD is recrystallized by essentially the same method used to prepare the Form 1 crystals described above. For example, recrystallisation using acetone and di-n-butyl ether gives crystalline AD in acetone at about 0.2-0.4 g / mL, about 2
This is accomplished by dissolving at 0-35 ° C, followed by removal of undissolved components, if necessary, for example by filtering or centrifuging the solution, which is usually hazy. Undissolved components are typically mono (PO
M) PMEA. The solution is then warmed to about 35-40 ° C. and the crystals initially used for recrystallization 0.2 to
About 5.2 to 6.2 mL per 0.4 g (usually about 5.7
(mL) warm (about 35-40 ° C.) di-n-butyl ether is added. The recrystallized mixture is then cooled to room temperature over about 4-4.5 hours. The recrystallisation mixture has a relatively small volume, for example about 1-3 L, when used,
Cool to room temperature faster. The time to cool the mixture is not critical and can vary.

Generally, recrystallization begins shortly after the addition and mixing of the di-n-butyl ether is complete, then recrystallization is allowed to proceed for about 4 to 36 hours, usually about 6 to 24 hours. Crystals further obtained from recrystallization at room temperature for about 4 to 36 hours are usually obtained by recrystallization at about 4 to 10 ° C.
It is obtained by cooling to room temperature and leaving the mixture at low temperature for about 1 to 6 hours. AD usually used for recrystallization
Is sufficient to form a saturated or nearly saturated solution, i.e. about 0.4 g /% using acetone.
It is mL. The dissolution of AD in acetone is completed in about 2-8 minutes with moderate agitation. The material that remains undissolved after this initial mixing period is removed and discarded, and then a less polar second solvent of the solvent pair is added to the mixture containing the first crystallization solvent.

If desired, the Form 1 crystals are recrystallized using a single solvent such as acetone. In this embodiment, sufficient crystals are dissolved in a solvent at room temperature to give a saturated or nearly saturated solution, followed by removal of undissolved organisms. The mixture is then warmed to 35 ° C. and it is allowed to cool as described for recrystallization using acetone and di-n-butyl ether solvent pair.

Recrystallization of Form 2 crystals proceeds as described for recrystallization of Form 1 crystals, but using Form 2 crystals dissolved in a recrystallization solvent. The Form 1 crystals resulting from the recrystallization are optionally converted to Form 2 crystals as described herein for the conversion of Form 1 to Form 2 crystals. Recrystallization from Form 2 to Form 1 crystals can also be accomplished. In this case, molecular sieves or other solvent drying means are optionally used to reduce the amount of water present after the Form 2 crystals are dissolved in the first solvent and during the recrystallization process. obtain. Form 2 crystals are also recrystallized using a solvent containing about 1-2% water to directly obtain Form 2 crystals.

Recrystallisation of Form 3 in methanol is carried out in the same manner as described herein for the preparation of Form 3 crystals. Saturated or nearly saturated methanolic solution, ie, at least about 0.6 g / mL AD,
Used to prepare crystals.

Salts are prepared, if desired, by acid addition of certain organic and inorganic acids to the basic center on the adenosine of AD. Generally, acid salts are prepared by standard methods, which comprises dissolving AD free base in an aqueous, aqueous-alcohol, or aqueous-organic solution containing the selected acid or acid counterion, Including with optional crystallization, and optionally evaporation, stirring, or cooling of the solution. Usually, the free base is reacted in an organic solution containing an acid or counterion, in which case the salt is usually separated directly or the solution is seeded with crystals or concentrated to precipitate the salt. Can be easy. Embodiments include AD,
The solvent (usually crystallization solvent) containing a solution containing, and sulfonic acids _(e.g., C _{6 ~ 16} aryl sulfonic _acids, C _{4 ~ 16} heteroaryl sulfonic acid or the like _C 1 _{~ 16} alkyl sulfonic acids). Embodiments also include AD,
Includes a solution containing a solvent (usually a crystallization solvent) and a carboxylic acid (eg, any such carboxylic acid, such as a tricarboxylic acid, dicarboxylic acid, or monocarboxylic acid, containing about 1 to 12 carbon atoms). .

Pharmaceutical Formulations and Routes of Administration The compositions of the present invention, which typically include Form 1 of crystalline AD (hereinbelow referred to as the active ingredient), will be administered to the situation to be treated. Administration by any suitable route, suitable routes include
Oral, rectal, nasal, topical (including eye, cheek, and sublingual), vaginal, and parenteral (subcutaneous, intramuscular, intravenous, intradermal,
(Including submeningeal and epidural). Generally, the compositions of the invention are administered orally, but compositions containing crystalline AD can be administered by any of the other routes noted above.

While it is possible for AD to be administered as the pure compound, it is preferable to present it as a pharmaceutical formulation. The formulations of the present invention comprise AD, together with one or more pharmaceutically acceptable excipients or carriers ("acceptable excipients"), and optionally other therapeutic ingredients. including. The excipient (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

Formulations include those suitable for local or systemic administration, which may be oral, rectal, nasal, buccal, sublingual, vaginal, or parenteral (subcutaneous, intramuscular, intravenous). (Including intra-, intra-dermal, sub-meningeal and epidural) administration. The formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with the carrier or excipient which constitutes one or more accessory ingredients.
In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, drying or shaping the product. It

Formulations of the present invention suitable for oral administration may be prepared as discrete units such as sachets, cachets, or tablets, each containing a predetermined amount of active ingredient; powder or granules. As; solutions or suspensions of aqueous or non-aqueous liquids; or as oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient may also be presented as a pill, electuary or ointment.

The formulations of the present invention include compositions that include AD and an acceptable excipient. Such excipients include binders, diluents, disintegrants, preservatives, dispersants, glidants (gli).
dants) (anti-adhesives), and lubricants. Such compositions optionally contain unit doses including tablets and capsules. Such a composition may, if desired,
Includes tablets containing about 5-250 mg, usually about 5-150 mg AD, about 60 mg or 120 per tablet.
Includes tablets containing mg. Such tablets optionally contain about 1-10% binder, about 0.5-10% disintegrant, about 50-60% diluent, or about 0.25-5%.
Including lubricant. Such compositions also include a liquid (eg, water), AD, and one or more acceptable excipients selected from the group consisting of binders, diluents, dispersants, and disintegrating agents. , Including wet granules.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients or excipients. Tablets are typically about 5 per tablet
-250 mg, usually about 30-120 mg, and usually predominantly crystalline AD of Form 1 (eg, about 60 mg per tablet, or about 12 mg per tablet).
0 mg Form 1 AD), where only a limited amount (usually less than about 20%) of Form 2 crystals, other crystal forms,
Or there is amorphous AD. Compressed tablets can be prepared by a suitable machine with AD in free flowing form, such as powder or granules, optionally with binders, disintegrants, lubricants,
It can be prepared by mixing with an inert diluent, preservative, surfactant, or dispersant and compressing. Molded tablets may be made by molding in a suitable machine, a mixture of powdered compound, usually moistened with a liquid diluent. Tablets may be coated and printed, embossed or scored as necessary and formulated to provide a slow or controlled release of the active ingredient therein. Can be done. Embodiments include crystalline AD, typically Form 1 or Form 2, and acceptable excipients (eg, lactose, pregelatinized starch, croscarmelose sodium.
m), talc, and dry, wet granules containing magnesium stearate).

Formulations containing crystalline AD and excipient (s) may also include L-carnitine or a salt of L-carnitine, such as L-carnitine-L-tartrate (2: 1). Release of pivalate from the pivaloyloxymethyl moiety of AD in vivo appears to reduce L-carnitine levels in patients. Tablets containing L-carnitine-L-tartrate and AD may reduce the effect of pivalate on L-carnitine depletion in patients taking AD. The amount of L-carnitine to be included will be apparent to the clinician considering the degree of exhaustion in the patient.

Typical formulation ingredients for tablets or related dosage forms comprise one or more binders, diluents, disintegrants, or lubricants. These excipients are
It increases the stability of the formulation and promotes tablet compression during manufacture or disintegration of the formulation after ingestion. Tablets are typically formed by wet granulating one or more excipients with AD in a mixture, followed by wet milling the granules and drying until the reduction on drying is about 3% or less. Created. Better processing aids, such as pregelatinized starch or povidone, are optionally present at levels of about 1-10%. Microcrystalline cellulose or sodium coscarmellose (coscarm)
Disintegrants, such as cross-linked celluloses, such as the rose sodium) are optionally present at levels of about 0.5-5% to facilitate tablet disintegration. Diluents such as monosaccharides or disaccharides are optionally present at levels of about 40-60% to mask the physical properties of AD or to facilitate tablet disintegration. A lubricant such as magnesium stearate, talc, or silicon dioxide is optionally present at a level of about 0.25-10% to facilitate tablet ejection during manufacture. Tablets may optionally include scavengers such as lysine or gelatin to trap formaldehyde which may be released upon storage of AD. Excipients have been described below; eg, research paper on "Starch before gelatinization", Handbook of P.
pharmaceutical Excipients,
Second Edition, American Pharmaceutical
al Association, 1994, 491-4
Page 93; Research paper on "Croscarmellose Sodium", Handbook of Pharmace.
organic Excipients, 2nd edition, Ame
rican Pharmaceutical Asso
Citation, 1994, 141-142; Research paper on "Lactose monohydrate", Handboo.
k of Pharmaceutical Excip
ients, 2nd edition, American Pharma
scientific Association, 199
4, pp.252-261; Research paper on "Talc", Handbook of Pharmaceuti.
cal Excipients, 2nd edition, American
an Pharmaceutical Associa
Tion, 1994, pp. 519-521; Research paper on "Magnesium stearate", Handboo.
k of Pharmaceutical Excip
ients, 2nd edition, American Pharma
scientificAssociation, 1994,
280 to 282 pages.

A representative container for storage of Form 1 AD formulations limits the amount of water present in the container. A typical unit dosage or dosage will be packaged with a desiccant such as silica gel or activated carbon, or both. Containers are typically induction sealed
n sealed). Silica gel-only packaging is a sufficient desiccant for storage of tablets containing AD at ambient temperature. AD contains two pivaloyloxymethyl moieties per molecule. Thus, silica gel is suitable as a single desiccant for compounds such as therapeutic agents containing one or more pivaloyloxymethyl moieties. The water permeation properties of the container have been described below; eg Cont
ainers--Permeation, chapter, USP
23, United States Pharmaco
peer Convention, Inc. , 126
01 Twinbrook Parkway, Rock
Ville, MD 20852, p. 1787 (199
5).

For infections of the eye or other surface tissues, for example mouth and skin, the formulations preferably contain, for example, 0.01-10% w / w (ranging between 0.1% and 5%, 0.1% w such as 0.6% w / w, 0.7% w / w
Of active ingredient (s) in increments of / w, preferably 0.2-3% w / w, and most preferably 0.5-2% w / w. Applied as a topical ointment or cream containing one or more). When formulated in an ointment, the active ingredients may be used with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

If desired, the cream-based aqueous phase may be
For example, at least 30% w / w polyhydric alcohols, ie alcohols with two or more hydroxyl groups (eg propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG400). ,
As well as mixtures thereof). Topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
Examples of such epithelial penetration enhancers include dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of the present invention may be composed of known ingredients in a known manner. The phase may contain only emulsifiers (otherwise known as excretion enhancers), but it preferably comprises a mixture of at least one emulsifier, with a fat or oil, or both a fat and an oil. Preferably a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both oils and fats. Together, the emulsifier (s) with or without stabilizer (s) make up the emulsifying wax, and the wax makes up the emulsifying ointment base with the oil and fat. This forms the oily dispersed phase of the cream formulation.

Elimination enhancers and emulsion stabilizers suitable for use in the formulations of the invention are Tween®.
60, Span® 80, cetostearyl alcohol,
Includes benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

The choice of suitable oil or fat for the formulation is based on achieving the desired cosmetic properties. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Linear or branched mono- or di-basic alkyl ester (for example, diisoadipate ester, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitine 2-ethylhexyl acid, or C
A blend of branched chain esters known as rodamol CAP) can be used, with the last three being the preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include
Includes eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is present in such formulations in an amount of 0.01-20
%, In some embodiments 0.1-10.
%, And at about 1.0% w / w in others, are suitably present.

Formulations suitable for topical administration in the mouth include the following: lozenges with the active ingredient in a flavored base (usually sucrose and acacia) or tragacanth; gelatin and glycerin, or sucrose and Pastilles containing the active ingredient in an inert base such as acacia; as well as mouth rinses containing the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base including, for example, cocoa oil or salicylic acid.

Formulations suitable for nasal or inhalation administration, where the carrier is a solid, include powders with a particle size in the range, for example, 1-500 microns (30 microns,
2 increments of 5 microns, such as 35 microns
Including a particle size range between 0 and 500). Formulations suitable for administration when the carrier is a liquid, for example as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and delivered with other therapeutic agents. Inhalation therapy is easily administered by metered dose inhalers.

Formulations suitable for vaginal administration include vaginal suppositories, tampons, creams, gels, pastes, foams, or, in addition to the active ingredient, such carriers as are known in the art to be appropriate. It can be presented as a spray formulation.

Formulations suitable for parenteral administration are sterile and include aqueous or non-aqueous injection solutions. This may include anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, suspensions and Thickeners may be included. The formulations may be presented in containers containing unit doses or multiple doses, such as sealed ampoule tubes, and vials with elastomeric fasteners, and may be stored in sterile liquid carriers, eg, for injection, immediately before use. Can be stored in the lyophilized state, requiring only the addition of water). Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit sub-dose, as recited above, or an appropriate fraction thereof, of the active ingredient.

In addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art relevant to the type of formulation in question, such as those suitable for oral administration. Flavoring agents may be included.

The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with their veterinary carrier.

Veterinary carriers are materials that are useful for the purpose of administering the composition to cats, dogs, horses, rabbits, and other animals, and may be solid, liquid, or gaseous materials. In other words, they are inert or acceptable in the field of veterinary medicine and are compatible with the active ingredients. These veterinary compositions may be administered orally, parenterally or by any other desired route.

The compounds of the present invention can be used to provide sustained release pharmaceutical formulations comprising a matrix or absorbable material and one or more compounds of the present invention as the active ingredient, wherein the active compound is active. The release of the components can be controlled and regulated to provide less frequent dosing or to improve the pharmacokinetic or toxicity profile of the compound. Sustained-release preparations adapted for oral administration which contain one or more compounds of the invention in discrete units may be prepared according to conventional methods.

All references listed herein are expressly incorporated by reference with limitation.

[0164]

The following examples further illustrate, but do not limit, the present invention.

Example 1. Preparation of Form 1 crystals. In a 500 ml single neck round bottom flask equipped with a magnetic stir bar, add PME
A (27.3 g, 100 mmol) was added. Under nitrogen,
To this was added N-methylpyrrolidinone (109.3 mL) and triethylamine (50.6 g, 69.8 mL, 5
00 mmol) and the resulting suspension was stirred vigorously. Chloromethyl pivalate (75.2 g, 72.
0 mL, 500 mmol) was added and the stirring suspension was placed in a 45 ° C. oil bath for 18.5 h. The resulting thick pale yellow suspension is converted to isopropyl acetate (1.0
L) and stirred for 1 hour. Solids were removed by filtration (Kimax glass funnel with "C" glass frit) and further isopropyl acetate (2
It was washed with 50 mL). The washings were combined with the filtrate and the organic phase was extracted with water (200 mL x 2). The aqueous extracts were combined and back extracted with isopropyl acetate (25
0 mL x 2). 1975m when all organic phases are combined
It became L. Isopropyl acetate was added to bring the total volume of the organic phase to 2.0 L. For the purpose of internal control for this experiment, the organic phase was divided into two 1.0 L aliquots. One side
Work up using a brine wash and sodium sulphate treatment, the other proceeded without these steps (see below).

A 1.0 L sample of the organic phase for this new procedure was run using a standard (Buchi) rotary evaporator at 45 ° C. bath temperature and 50-7 throughout the procedure.
Concentrate directly to an oil using a 0 mm vacuum. The oil weighed 32.4 g and appeared to be completely clear with no visible salt present. The oil was diluted with acetone (25 mL) to give a completely clear solution with no visible salts again visible. After standing at room temperature for about 3 hours, the solution remained completely clear. Place this solution in an oil bath set at 45 ° C,
Then, di-n-butyl ether (140 mL) was slowly added while keeping the internal temperature near 40 ° C. The flask was then removed from the oil bath and allowed to cool to room temperature,
After stirring at room temperature for about 16 hours, a precipitate of Form 1 AD was obtained. The solid product was collected by filtration (Kimax glass funnel with "M" glass frit). 90% solid
10% solution of acetone in di-n-butyl ether (v
/ V) (40 mL) and 1 in a vacuum oven
Dry for 2 hours (ambient temperature, nitrogen bleed, 28 "vacuum). This gave 12.2 g of a white solid (48.8% theoretical yield based on 50 mmol reaction scale).
Identified as 99.8% pure AD relative to external standard (HPLC). The remaining 1.0 L of organic phase was used as a control for the above results and worked up as follows. The organic phase was washed with brine (25 mL), dried over sodium sulfate (25 g, dry time 12 h) and concentrated as described above. This gave 27.4 g of oil, which was added as described above in acetone (25 mL) and butyl ether (13 mL).
(5 mL). The solid was collected by filtration and dried as described above to give 12.3 g of white solid (theoretical yield 48.9%), 9 relative to the external standard.
Identified as AD with 8.7% purity (HPLC).

Example 2. Preparation of Form 1 crystals. Glass-lined 30 gallon steel reactor (Pfaudle
r, Rochester, NY, model number P20-3
0-150-115) at room temperature in an amount of 9.7 kg of NMP.
To 3 kg of PMEA, and after adding NMP,
The mixture was stirred moderately. The medium agitation used was
It was sufficient to keep the solid PMEA in suspension and to prevent the contents of the reaction vessel from splashing on the wall. Then 5.6 kg TEA was added, followed by 8.3 k
g of chloromethyl pivalate was added. An additional 2.7 kg of NMP was then added to wash residual material from the transport line used to feed the reaction vessel. About 4
Adjust to 8 ° C and increase temperature to 18 with moderate stirring.
Maintained for a time of 38-48 ° C. After the reaction is complete,
Add 48 kg of isopropyl acetate to the reaction vessel at room temperature,
The resulting mixture is then stirred with moderate stirring at 43
Maintain at ˜48 ° C. for 1 hour, then filter to remove solids (Tyvek® filter, diameter 15.
5 ", Kavon Filter Products,
Wall, NJ, model number 1058-D). The 30 gallon container was first washed with an additional 12 kg of isopropyl acetate through a filter. The filtrate was lined with glass 5
Transferred to a 0 gallon steel reaction vessel (Pfaudler, model number P24-50-150-105) while maintaining the temperature at 43-48 ° C. The temperature was reduced to room temperature during the following steps. The mixture is then treated with 22 kg of water for about 1.5
Washed by vigorous stirring for ~ 2 minutes. The stirring was stopped and the phases were allowed to separate completely (about 10 minutes). The lower aqueous phase (about 26 L) was transferred to a glass-lined 30 gallon steel reaction vessel. Another 22 kg of water was added to the organic phase remaining in the 50 gallon reaction vessel and the phase was added to about 1.5
Stir vigorously for ~ 2 minutes. The stirring was stopped and the phases were allowed to separate completely (approximately 1 hour 40 minutes). The lower aqueous phase was transferred to a glass-lined 30 gallon steel reaction vessel, where it contained both the aqueous wash. Add 24 kg of isopropyl acetate to the aqueous wash in a 30 gallon reaction vessel,
The phases were then stirred vigorously for about 1.5-2 minutes, followed by stopping the stirring for a sufficient time to allow complete phase separation (about 10
Minutes). The upper organic phase was retained and mixed with the organic phase previously retained in the 50 gallon reaction vessel. 24k
g of isopropyl acetate was added to the aqueous wash in a 30 gallon reaction vessel, and the phases were vigorously stirred for about 1.5-2 minutes, followed by sufficient agitation to allow complete phase separation. (About 20 minutes). Leave the upper organic phase, and 5
It was mixed with the organic phase previously left in a 0 gallon reaction vessel. The combined organic phases were then combined with a brine solution (7 kg
Of water, 3.9 kg of NaCl) for about 1.5 to 2 minutes with vigorous stirring, followed by stopping the stirring and allowing the phases to separate completely (about 5 minutes). The brine phase was discarded. 1
8 kg of sodium sulphate was added to the reaction vessel and the mixture was stirred vigorously for about 1.5-2 minutes then allowed to stand for 1 hour. The organic phase weighed 98.5 kg at this point.

The contents of the reaction vessel were then gently agitated and bag filter (American Fe).
lt and Filter Co. , Model number RM
It was filtered through CS / S 122). The organic solution containing AD was transferred to a clean 50 gallon reaction vessel, and the volatile organics were removed at 26-30 "Hg vacuum at 33-41 ° C until 50-55 L of condensate was collected. The organic phase was removed from the 50 gallon reaction vessel to a clean 30 gallon reaction vessel with a cartridge filter (Memtec) containing a spun cotton cloth cartridge.
America, Corp. , Model number 91004
4) via vacuum filtration and washed first with 8.6 kg isopropyl acetate. The solution was kept at 5 ° C. overnight, then concentrated under reduced pressure at 26 ° C.-41 ° C. for 3 hours, about
L oil was obtained. 5.4 kg of acetone was added to the oil to give a clear solution. The solution was then stirred and warmed to 43 ° C. and 27 kg room temperature di-n-butyl ether was added over about 4 minutes, followed by warming to 43 ° C.
It returned to ℃. An additional 15 kg of di-n-butyl ether was added over about 4 minutes and the temperature returned to 43 ° C-44 ° C. From this point, the temperature is increased to 20 hours over about 7 hours and 15 minutes.
It was lowered to ℃. During this time, crystals of AD formed in the reaction vessel. The crystals were collected by filtration (Buchner funnel) and dried. 2.40 kg of AD was obtained (45.1
%). Example 3. Preparation of Form 1 crystals. A 12 L 3-neck round bottom flask was charged with 546.3 g of PMEA (2 mol) followed by 2.18 L of NMP at room temperature. Start mechanical gentle agitation (sufficient to keep solid PMEA in suspension but do not bounce contents of flask) to suspend PMEA, then 1.3.
9 L TEA was charged to the flask, followed by 1.44 L pivaloyloxymethyl chloride. The flask was then purged with nitrogen and the reaction was heated to 60 ° C for 30-45 minutes. The reaction system was maintained at 60 ° C. with gentle stirring for 2 to 2.5 hours. HPLC for completion of reaction
Confirmed by. Add 7.48 L of cold (0-3
The reaction was stopped by adding isopropyl acetate. At this time, the yield of AD is range-normalized (area
It reached 65-68% by normalization. Agitation was increased to moderate agitation (moderate vortex, but no content bounce), and the mixture was maintained at room temperature for 30 minutes with moderate agitation. During this time solids (eg TEA.HCl, mono (POM) PMEA) precipitated out of solution.

The reaction mixture was then mixed with a sintered glass funnel (4
0-60 μm) and the filter cake was washed with 2.51 L of isopropyl acetate at room temperature.

The filtrate was then extracted twice with 2.0 L of drinking water at room temperature. The combined aqueous phases were back-extracted twice with 2.51 L of isopropyl acetate (room temperature). All organic phases were combined and extracted once with 985 mL of drinking water. The organic phase is isolated and 35-39 at a vacuum of about 30 mm Hg.
Concentration under reduced pressure at a temperature of ° C for about 1-2 hours gave 1.24 kg of a yellow oil.

The oil was transferred to a 12 L 3-neck flask,
And it cooled to room temperature over about 30 minutes. 6 in a flask
Add 28 mL of room temperature acetone, then 3.14 L
Of di-n-butyl ether was added. Start slow stirring and allow the solution to reach 35 ° C. for about 5-20 minutes.
Heated to. When the temperature reached 35 ° C, the heating was stopped and the temperature was not raised any further. The solution was cooled to below 30 ° C (20-29 ° C) over about 30 minutes. During the cooling period, crystals of Form 1 were formed in the crystallization mixture with continued stirring at room temperature followed by 14-2.
Slow stirring was continued for 0 hours. The crystals were then filtered (Tyvek® filter) and the filter cake was washed with 2 L of 10% acetone 90% di-n-.
It was washed with a butyl ether (v / v) solution. The cake was dried in a drying oven with nitrogen sparging at room temperature until constant weight was obtained (about 2 days).

The yield of AD of the obtained Form 1 was PMEA.
The more theoretical yield was 50-54%, and the purity was 97-98.5% by HPLC by range normalization.

Example 4. Preparation of Form 1 crystals. A 3 L 3-neck round bottom flask was charged with 273.14 g of PMEA (1 mol) followed by 1.09 L of NMP at room temperature. Slow mechanical agitation (solid PMEA
Is sufficient to keep the suspension in place but does not bounce the contents of the flask) to suspend the PMEA, then 0.418 L TEA (3 eq) is charged to the flask, Then 0.72 L of pivaloyloxymethyl chloride (5 eq) was added. The flask was then purged with nitrogen and the reaction was allowed to 60 for 30-45 minutes.
Heated to ° C. The reaction system is 60 ° C, and gentle stirring is performed for 2 to
Maintained for 2.5 hours. The completion of the reaction was confirmed by HPLC. The reaction was stopped by adding 3.74 L of cold (0-3 ° C.) isopropyl acetate to the flask. At this time, the yield of AD is range normalized (area normal).
It was 68-70% by ization). The agitation was increased to moderate agitation (moderate vortex, but no bounce of contents) and the mixture was left at room temperature for 30 minutes with moderate agitation. During this time a solid (eg TEA
HCl, mono (POM) PMEA) precipitated out of solution. The reaction mixture was filtered using a sintered glass funnel (40-60 μm) and 1.26 L of filter cake.
It was washed with isopropyl acetate (room temperature). The filtrate was then extracted twice with 1.01 L of drinking water for each extraction at room temperature. The combined aqueous phases were back-extracted twice with 1.26 L of isopropyl acetate (room temperature). All organic phases were combined and extracted once with 492 mL of drinking water. The organic phase was isolated and concentrated under reduced pressure of about 30 mm Hg at a temperature of 35-39 ° C. for about 1-2 hours to give 0.6 kg of a yellow oil. The oil was transferred to a 3 L 3-neck flask and cooled to room temperature by lowering the temperature over about 30 minutes. Then add 314 mL of acetone (room temperature) to the flask.
Was added, and then 1.57 L of di-n-butyl ether was added. Slow stirring was started and the solution was heated to 35 ° C. for about 5-20 minutes. Temperature is 35 ° C
When the temperature reached, the heating was stopped and the temperature was not raised. The solution is cooled below 30 ° C. (20-29
(° C). During the cooling period, crystals of Form 1 formed in the crystallization mixture while continuing slow stirring. Another 1.15 L of room temperature di-n-butyl ether was added to the crystallization mixture. Medium stirring was continued at room temperature for about 16 hours. The crystals are then filtered (Tyvek
(Registered trademark) filter, and cake with 1 L of 10
% Acetone 90% di-n-butyl ether (v / v) solution, then the solution was removed by filtration. Cake the cake in a drying oven at room temperature with a stream of nitrogen.
Dry until constant weight is obtained (about 2 days).

The yield of the obtained Form 1 AD was PMEA.
From 55 to 58% of the theoretical yield from
From the range normalization, it was 99 to 100% by HPLC.

Example 5. Preparation of crystals of AD using isopropyl acetate as crystallization solvent. 43.7 at room temperature under nitrogen in a 500 mL three-necked flask equipped with a stirrer.
mL of NMP was added to PMEA (10.93 g). The mixture was stirred to suspend PMEA. Then TEA (27.9 mL) was added at room temperature, followed by pivaloyloxymethyl chloride (28.9 mL) at room temperature. The temperature was raised to 45 ° C and the suspension was stirred at 45 ° C for 12 hours. The resulting thick yellow suspension was diluted with isopropyl acetate (150 mL) at room temperature and stirred vigorously for 75 minutes at room temperature. The solid was removed by filtration through a "C" sintered glass frit and the solid at room temperature 50 m
Wash with L of isopropyl acetate. The filtrates were combined and washed twice with deionized water, using 40 mL per wash. The combined washes were back-extracted twice with 40 mL of isopropyl acetate per extraction. All organic phases were combined, washed once with 20 mL deionized water, and the aqueous and organic phases were separated and left in contact for 2 hours at 17 ° C. During this time, long columnar crystals were observed to form at the water phase-organic phase interface. The crystals were collected by filtration using an "M" sintered glass frit and dried to give 512 mg of long columnar crystals.

Example 6. Analysis of AD by HPLC. Crystalline Form 1 AD for assessing purity, for isolating or identifying by-products, and AD
Was analyzed by HPLC to illustrate the use of by-products as a reference standard for The level of compound present was analyzed by the range normalization method. HPLC analysis was performed within 12 hours of standard or sample preparation.

A liquid chromatograph equipped with a fixed amount sample injector, a variable wavelength absorbance detector and an electronic integrator was used as a column (Alltech Mixed Mod).
eAnion Exchange (registered trademark) C8,
7 μm, pore size 100 Å, 250 mm x 4.6 mm (inner diameter), Alltech, Deerfield, IL),
And guard column (20 mm x 4.6 mm (inner diameter),
Dry-filled with Pellicular C8 particles, Allt
ech, Deerfield, IL). Chromatographic quality water was used. The chemicals used were chromatography grade acetonitrile (Burdick & Jackson, Musk
egon, MI), anhydrous analytical grade potassium dihydrogen phosphate (potassium phosphate)
monobasic) (KH ₂ PO ₄ , Mallinc)
krdot, Paris, KY), anhydrous analytical grade dipotassium hydrogen phosphate (potassium pho)
spherate dibasic (K ₂ HPO ₄ , Ma
Llinckrodt, Paris, KY), and A. C. S. Reagent grade phosphoric acid (Mallinck
rodt, Paris, KY). Aqueous potassium phosphate solution should be filtered (0.45 μm nylon 6 before use).
6 membrane filter, Rainin, Woburn, MA)
And degassed. Equivalents of these components and compounds can also be used. Equivalent devices and / or reagents can also be used to achieve similar results.

Mobile phase A consisting of potassium phosphate buffer (pH 6.0: acetonitrile 70:30 v / v)
1400 mL of 200 mM potassium phosphate buffer (pH
6.0) was mixed with 600 mL of acetonitrile. Potassium phosphate buffer (pH 6.
Mobile phase B consisting of 0: acetonitrile 50:50 v / v) was prepared by mixing 1000 mL of 200 mM potassium phosphate buffer (pH 6.0) with 1000 mL of acetonitrile.

Prior to analysis of the sample, the HPLC column was loaded with mobile phase A at 1.2 mL per minute for 1 hour at room temperature.
Equilibrated with. 5 μL of AD sample containing by-products
(About 1 mg / mL solution) at room temperature and 100 for 1 min.
% Mobile phase A was analyzed in a 25 minute run at a flow rate of 1.2 mL per minute, followed by a linear gradient to 100% mobile phase B in 19 minutes. Then column 10
Hold at 0% mobile phase B for 5 minutes.

A sample containing AD was treated with about 25 mg of AD.
Accurately weigh samples or preparations, and AD
Was prepared by dissolving in a final volume of 25.0 mL of sample solvent. 800 mL of 200 mL of potassium phosphate buffer (3.40 g of potassium dihydrogen phosphate per 1 L of water, adjusted to pH 3.0 with phosphoric acid) was used as the sample solvent.
Prepared by mixing with mL of acetonitrile and equilibrating to room temperature. Compounds are identified based on their elution time and / or their retention time. AD usually elutes from such a gradient at about 9.8 minutes, mono (POM) PMEA at about 6.7 minutes, and PM
EA elutes in about 3.5 minutes.

Example 7. Physical characterization of Form 1 crystals. The crystals of Form 1 were placed in an aluminum holder mounted in a diffractometer (GE Model XRD-5 automated with Nicolet automation package) at about 100-1.
Analyzed by XRD by loading 50 mg of crystals. Form 1 crystal is a standard focus copper pole X-ray tube (Vari
can CA-8) with a graphite monochromator (ES Industries) and scintillation detector at 40 KV and -20 m.
By exposing to the X-ray generator operated in A, 1.5
Scanning was performed at an angle 2θ between 4 ° and 35 ° with a scan rate of 0.05 ° per second. X used for calculation
The weighted average value of the wavelength of the line is 1.541838 of CuKα.
It was Å. Form 1 AD crystal has a morphology of about 6.
9, 11.8, 12.7, 15.7, 17.2, 20.
Characteristic XRD peaks appearing at 7, 21.5, 22.5, and 23.3 are shown. Exemplary XR for Form 1
The D pattern is shown in FIG.

The Form 1 crystals were also analyzed by differential scanning calorimetry, and the temperature with a characteristic endothermic transition at approximately 102.0 ° C. with an onset at approximately 99.8 ° C., as shown in FIG. The record was shown. Temperature recording under nitrogen atmosphere,
Obtained using a scan rate of 10 ° C. per minute. The sample was not sealed in the vessel of the DSC instrument and instead was analyzed in the DSC instrument at atmospheric pressure. Differential scanning calorimeter (TA Inst
obtained by using a model DSC2910) with a controller of the models, RUM. Approximately 5 mg AD was used to obtain the temperature record. Differential scanning calorimetry has been described (eg, US Ph.
armacopoea, Volume 23, 1995, Method 8
91, U. S. P. Pharmacopeal Co
nvention, Inc. , Rockville,
See MD).

The melting point of Form 1 crystals was determined by conventional melting point analysis. The analysis was carried out using a Mettler model FP 90 Central equipped with a model FP81 measuring cell.
It was performed using the processor according to the manufacturer's instructions. The sample was equilibrated for 30 seconds at a starting temperature of 63 ° C, followed by increasing the temperature at 1.0 ° C / min. Form 1 crystals melted over the range 99.1 ° C to 100.7 ° C.

The infrared absorption (IR) spectrum of the crystal of Form 1 was analyzed by Perkin-Elmer model 1650 FT.
Obtained using an IR spectrophotometer according to the manufacturer's instructions. Two translucent pellets containing about 10 wt% (5 mg) of Form 1 crystals and about 90 wt% (50 mg) dry (60 ° C. under reduced pressure overnight) potassium bromide (Aldrich, IR grade) were prepared. It was prepared by grinding two powders together to obtain a fine powder. IR spectroscopy has been described (eg, US Phar, for example).
macopoeia, Volume 23, 1995, Method 19
7, U. S. P. Pharmacopeal Con
Vention, Inc. , Rockville, M
D; Morrison, R .; T. Et al, Organic
Chemistry, 3rd edition, Allyn and
Bacon, Inc. , Boston, 405-41
See page 2, 1973). Before scanning with the sample, place the spectrophotometer sample chamber at approximately 6
p. s. Purge i high purity nitrogen gas for at least 5 minutes to reduce the interference of carbon dioxide absorption in the background scan to <3%. Form 1 crystals are approximately 3 in reciprocal centimeters in potassium bromide.
325-3275, 3050, 2800-1750, 1
700, 1625, 1575-1525, 1200-1
Infrared absorption spectra having characteristic bands appearing at 150, 1075, and 875 are shown. An exemplary infrared absorption spectrum for Form 1 is shown in FIG.

Form 1 crystals usually appear as an opaque white or off-white powder when dried. The crystals obtained from a given preparation are usually polydisperse, and crystal habits that include tablet crystals, needle crystals, plate crystals, and agglomerates of tablet crystals, needle crystals, and plate crystals. Has a range of. Form 1 crystals typically range in length from about 1 μm to about 300 μm in length, and are in the form of tablets with exceptionally cracked or angled edges. Acetone and di-n-as crystallization solvents
From the preparation using butyl ether, low temperature (usually about 2
The crystals of Form 1 obtained at ~ 4 ° C) are typically agglomerates, they contain predominantly needles and some tabular crystals. Figures 4-7 show crystals of Form 1 obtained from crystallization in acetone and di-n-butyl ether at temperatures above 15 ° C. These photographs show tablets or plate-like and needle-like crystals that range in length from about 10 μm to about 250 μm. Figure 9
Figure 2 is a photograph showing Form 1 crystals obtained from crystallization in acetone and di-n-butyl ether at temperatures between about 2-4. The photograph shows about 30 μm to about 1 in diameter.
Plate-like and needle-like crystal aggregates in the range of 20 μm are shown. The individual crystals in the agglomerates have angular edges.

Crystals of Form 1 are from Karl Fische
It was found to have a water content of less than 1% by r titration. We performed water content analysis essentially as described (eg, US Pharmaco.
Poea, 1990, pp. 1619-1621, U.S.P.
S. Pharmacopoeial Conventi
on).

Example 8. Preparation of Form 2 crystals. Form 1 crystals were converted to Form 2 dihydrate by incubating at room temperature for 3 days in air at 94% relative humidity. During the conversion of Form 1 to Form 2, a mixture of Form 1 and Form 2 crystals was obtained, which increased over time from Form 2 which was not detected in the original Form 1 preparation. At the end of the 3 day incubation, the final Form 2 preparation contained no detectable Form 1 crystals.

Example 9. Physical characterization of Form 2 crystals. Form 2 crystals were analyzed by XRD by the same method used for Form 1 crystals. Form 2 A
The D crystal has approximately 8.7 to 8.9, 9.6, and 2 in the angle 2θ.
16.3, 18.3, 18.9, 19.7, 21.0,
21.4, 22.0, 24.3, 27.9, 30.8,
And had a characteristic XRD peak appearing at 32.8. An exemplary XRD pattern for Form 2 is shown in FIG.

The Form 2 crystals were also analyzed by differential scanning calorimetry by the same method used to analyze the Form 1 crystals, and showed about 69., as shown in FIG.
It showed a thermogram with a characteristic endothermic transition at about 72.7 ° C with an onset at 5 ° C.

The melting point of Form 2 crystals was determined by conventional melting point analysis. The analysis was performed using the same method as described for Form 1. Form 2 crystals are 70.9 ° C
Melted over a range of ˜71.8 ° C.

The IR spectrum of the crystal of Form 2 is shown as Form 1
Was obtained using the same method as described for the crystals. The IR spectrum is shown in Figure 13 and shows the following characteristic absorption bands. These are the reciprocal centimeters of approximately 3300-3350, 3050, 2800-
1750, 1700, 1625, 1575 to 1525,
Appears in 1200-1150, 1075, and 875. These bands are similar to those associated with Form 1 crystals, but Form 2 is further at approximately 3500.
The OH bond stretching band accompanying water is shown.

Form 2 crystals are obtained from Karl Fische.
It was found to have a water content of 6.7% by r titration. We performed water content analysis essentially as described (eg, US Pharmaco.
Poea, 1990, pp. 1619-1621, U.S.P.
S. Pharmacopeial Conventio
n).

Example 10. Preparation of Form 3 crystals. Sufficient Form 1 crystals (about 250 mg) to obtain a solution,
It was dissolved in anhydrous methanol (about 2 mL) at room temperature. A solution was obtained by mixing for about 10-15 minutes until the crystals dissolved. Leave the solution for 10 to 48 hours without stirring,
Form 3 crystals were then recovered from the solution.

Example 11. Physical characterization of Form 3 crystals. Form 3 crystals were analyzed by XRD by the same method used for Form 1. A of crystalline form 3
The D crystal basically has an angle of about 8.1, 8.7,
14.1, 16.5, 17.0, 19.4, 21.1,
22.6, 23.4, 24.2, 25.4, and 3
It was characterized as having an XRD peak appearing at 0.9. An exemplary XRD pattern for Form 3 is shown in FIG.
Shown in.

Example 12. Synthesis and purification of PMEA.
The PMEA used for the synthesis and crystallization of AD is
Purified to increase product yield and purity. 54
A 12 L three-neck round bottom flask containing 8.8 g of diethyl PMEA was charged with 637.5 mL of acetonitrile at room temperature. Diethyl PMEA was dissolved with moderate agitation (moderate vortex, little or no splashing of flask contents). The flask was purged with nitrogen and 803.8 g of bromotrimethylsilane was added slowly (about 2-5 minutes). HPLC contents of the flask
The mixture was heated under reflux (65 ° C.) for 2 hours until the residual monoethyl PMEA was ≦ 1% by the range normalization analysis. Volatile components were distilled off at ≦ 80 ° C. and about 20 mm Hg. Next, 1500 mL of room temperature water was added to the flask. The pH of the solution in the flask is then adjusted to 25% w
Adjusted to 3.2 with NaOH / v. The flask contents were then heated to 75 ° C. for 2 hours and then the contents were 15-
Cool to 3-4 ° C over 20 minutes and 3-3.5 hours 3-4
It was kept at ℃. The flask contents were then filtered through a glass frit filter and the cake washed with 150 mL cold water (3-4 ° C). Washed cake, clean 1
Transfer to a 2 L three-necked flask and add 2025 to the flask.
mL of water was charged and the flask was heated to 75 ° C and held at that temperature for 2 hours. The heat was turned off and the flask was cooled and held at 3-4 ° C for 3-3.5 hours. Then
Filter the contents of the flask with a glass frit filter,
Then wash the cake with 150 mL of cold water (3-4 ° C.),
It was then washed with 1050 mL of room temperature acetone. The cake was dried to constant weight by heating at 65-70 ° C. at about 20 mm Hg. PMEA yields 99% by either range normalization or external standard HPLC analysis.
With a purity of 85.4%.

Example 13. Form 1 single crystal X-ray crystallography.

About 200 mg of lot 840-D-1 A
D drug substance was dissolved in 200 mg of acetone. The solution was heated to about 60 ° C. Ambient temperature di-n-butyl ether was added slowly to the solution at 60 ° C. until the first traces of precipitation appeared. The mixture was then shaken and reheated to about 60 ° C to form a clear and uniform solution. The solution was allowed to cool to ambient temperature overnight and kept at ambient temperature for about 2 days. The crystals obtained were very polydisperse, some having a length of up to 1 mm. The supernatant was decanted and the remaining crystals were washed with a total of about 1 mL of di-n-butyl ether over 4 cycles to remove residual supernatant. Crystals with dimensions of approximately 150 × 200 × 320 μm were subjected to analysis using single crystal X-ray diffraction.

Mo-Kα irradiation (λ = 0.71069Å) through a graphite monochromator for all measurements
Siemens SMART diffractometer (Si
emens Industrial Automati
on, Inc. , Madison, WI).
The crystals were mounted on glass fiber using Paratone N® hydrocarbon oil. Data acquisition was performed at -135 ± 1 ° C. Reciprocal space (recipr
The frames for any of the hemispheres were collected using a w scan of 0.3 ° per frame, counting 10 seconds per frame.

Measurement was completed up to 2θ of 51.6 ° 5
The 967 integrated reflections were averaged to obtain 3205 Friedel intrinsic reflections (R _int = 0.044). The structure was analyzed with accurate anisotropy without hydrogen atoms. A hydrogen atom was introduced at the idealized position. The final cycle of the full-squares least-squares optimization is 243 with I> 3σ
Based on 8 observed reflections and 306 variable parameters, convergence at R = 0.048 (R _w = 0.054).

In the range of 3.00 <2θ <45.00 °,
Using the measured positions of 3242 point reflections with I> 10σ, the lattice constants and orientation matrices obtained from the least-squares optimization matched the C-center monoclinic lattice specified below. : A = 12.85Å, b = 24.
50Å, c = 8.28Å, β = 100.2 °, Z = 4,
Space group Cc.

The following table shows the data obtained from the study. Diagrams of AD are shown in FIGS. 27 and 28.

[0202]

[Table 1]

[0203]

[Table 2]

[0204]

[Table 3] Example 14. Preparation of Form 4 crystals. Form 1 AD (1
0.05 g) was dissolved in isopropanol (50 mL) while warming (about 35 ° C.) and then filtered through a glass frit (M frit, ASTM 10-15 μm). The filtrate was added to a stirred solution of dissolved fumaric acid (2.33 g) in isopropanol (49 mL) at about 35 ° C. and the mixture was allowed to cool to room temperature. Form 4 crystals, AD fumaric acid (1: 1) formed spontaneously in the mixture shortly after the AD solution was added to the isopropanol solution. Crystals formed at room temperature for 2 days, were collected by filtration and were dried under vacuum at room temperature under nitrogen.

Example 15. Preparation of Form 4 crystals. Form 1
AD (1005.1 g) was dissolved in warm (about 45 ° C.) isopropanol (3.0 L). The warm AD solution was added to the stirred solution of isopropanol (6.0 L) containing dissolved fumaric acid (233.0 g) at about 45 ° C. in a 12 L flask over about 20 minutes with moderate stirring. The temperature of the mixture was maintained at 40-45 ° C. for 10 minutes, and the heating was stopped when many precipitates were formed. A few minutes after all the AD solution had been added, the mixture became cloudy and then a few minutes after which a lot of precipitate had formed, at which point the stirring was stopped (mixture temperature 42 ° C.). A precipitate was formed for several hours. Slow agitation was started and continued for about 2 hours, then a 12 L flask was submerged in room temperature water overnight with continued slow agitation to facilitate cooling of the mixture. The precipitate is first filtered (Tyvek®).
Filter) and a second filtration (M glass frit) and dried under vacuum at room temperature under nitrogen.

Example 16. Preparation of crystalline AD salts from organic and inorganic acids. Form 1 AD (500 mg, 1.0 m
mol) was dissolved in isopropyl alcohol (5 mL) while warming (<40 ° C.). 2 mL or acid (1.0 mmol) dissolved in a larger amount of isopropyl alcohol as needed to dissolve the acid, A
D solution. The solution was stored at room temperature in tightly capped scintillation vials. In some cases, precipitated salt was observed shortly after the solution was capped (about 1 minute). For other salts, precipitation started to form up to several months after the solution was capped.
The melting points for all 13 salts are shown below. The XRD data (angle 2θ) for the 9 salts are also shown below. The XRD data show most of the highest intensity peaks for these salts.

[0207]

[Table 4] Example 17. AD formulation. Form 1 AD with some excipients, 3 per tablet as follows:
Formulated in tablets containing 0, 60 or 120 mg AD.

[0208]

[Table 5] Tablets containing Form 1 AD were made by compounding croscarmellose sodium, pregelatinized starch, and lactose monohydrate in a granulator. Water was added and the contents were mixed in the granulator until a suitable wet granulation was formed. Grind wet granules and dry in a dryer 3
The dried granules were dried to a moisture content of less than% dry reduction and passed through a mill. The milled granules were combined with extragranular excipients (lactose monohydrate, croscarmellose sodium, and talc) and compounded in a compounder to give a powder formulation. Magnesium stearate was added, compounded in a compounder and compressed into tablets. Tablets were filled into high density polyethylene or glass bottles with polyester fiber packaging material and optionally silica gel desiccant.

Example 18. AD formulation. Form 1 AD was formulated with several excipients into tablets, each weighing 100 mg and containing either 25 or 50 mg AD per tablet, as follows. Tablets were prepared by wet granulation in a manner similar to that described above.

[0210]

[Table 6] The present invention provides crystalline forms of adefovir dipivoxil and methods for preparing crystals. The compositions and methods of the present invention have desirable properties for large-scale synthesis of crystalline adefovir dipivoxil or for their formulation during therapeutic dosing. The composition of the invention comprises an anhydrous crystalline form of adefovir dipivoxil.

[0211]

INDUSTRIAL APPLICABILITY According to the present invention, a composition comprising a novel form of adefovir dipivoxil having desirable properties for large-scale synthesis or for formulation into therapeutic dosing; Provided is adefovir dipivoxil, which has a good melting point and / or flow or bulk density properties to facilitate; adefovir dipivoxil, which has a storage stable form; adefovir dipivoxil, which can be readily filtered and easily dried.

Also provided is high purity adefovir dipivoxil having a purity of at least about 97% (w / w), and preferably at least about 98%.

Further provided is a method of synthesizing adefovir dipivoxil that removes or minimizes byproducts created during the synthesis of adefovir dipivoxil.

A method of purifying adefovir dipivoxil without the use of expensive and time consuming column chromatography is also provided.

[Brief description of drawings]

FIG. 1 shows an XRD pattern of Form 1 crystal.

FIG. 2 shows a temperature record obtained by differential scanning calorimetry of Form 1 crystals.

FIG. 3 shows a Fourier transform infrared absorption spectrum of the crystal of the form 1.

FIG. 4 is a photograph showing an embodiment of a crystal of Form 1 at 100 × magnification, which is a copy of the photograph made by stretching 128%.

FIG. 5 is a photograph showing an embodiment of Form 1 crystals at 100 × magnification, which is a copy of the photograph made by stretching 128%.

FIG. 6 is a photograph showing an embodiment of a crystal of Form 1 at 100 × magnification, which is a copy of the photograph made by stretching 128%.

FIG. 7 is a photograph showing an embodiment of Form 1 crystals at 100 × magnification, a reproduction of a photograph made with a 128% stretch.

FIG. 8 is a photograph showing an embodiment of a crystal of Form 1 at 100 × magnification, which is a copy of the photograph made by stretching 128%.

FIG. 9 is a photograph showing an embodiment of Form 1 crystals at 100 × magnification, a reproduction of a photograph made by stretching 128%.

FIG. 10 is a photograph showing an embodiment of a crystal of Form 1 at 100 × magnification, which is a reproduction of the photograph made by stretching 128%.

FIG. 11 shows an XRD pattern for Form 2 crystals.

FIG. 12 shows a temperature record obtained by differential scanning calorimetry of Form 2 crystals.

FIG. 13 shows a Fourier transform infrared absorption spectrum of the crystal of the form 2.

FIG. 14 shows an XRD pattern for Form 3 crystals.

FIG. 15 shows a temperature record obtained by differential scanning calorimetry of Form 3 crystals.

FIG. 16 shows an XRD pattern for Form 4 crystals.

FIG. 17 shows a temperature record obtained by differential scanning calorimetry of Form 4 crystals.

FIG. 18 shows an XRD pattern of crystals of AD hemisulfate.

FIG. 19 shows the XRD pattern of crystals of AD hydrobromide.

FIG. 20 shows an XRD pattern of crystals of AD nitrate.

FIG. 21 shows an XRD pattern of crystals of AD mesylate salt.

FIG. 22 shows an XRD pattern of crystals of AD ethyl sulfonate.

FIG. 23 shows an XRD pattern of crystals of ADβ-naphthylene sulfonate.

FIG. 24 shows an XRD pattern of crystals of ADα-naphthylene sulfonate.

FIG. 25 shows an XRD pattern of crystals of (S) -camphor sulfonate.

FIG. 26 shows an XRD pattern of crystals of AD succinate.

FIG. 27 is a schematic diagram of AD.

FIG. 28 is a schematic diagram of AD.

FIG. 29 shows an XRD pattern of AD.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI theme code (reference) A61P 31/22 A61P 31/22 // A61K 31/675 A61K 31/675 (72) Inventor Thomas Tee. Kei. Lee United States California 94065, Redwood City, Meridian Drive 300 (72) Inventor Lawrence Buoy. Manes United States California 94038, Mosque Beach, Winke Way 199 (72) Inventor John Dee. Manger Jr. United States California 95002, Albiso, Catherine Street 1044 (72) Inventor Ernest Jay. Presb United States California 94024, Los Altos, Richardson Avenue 1336 (72) Inventor Lisa Em. Schulz United States California 94070, San Carlos, Sycamore Street 234 (72) Inventor Duffin E. Kerry United States California 94122, San Francisco, 33 Rd Avenue 1404 F Term (reference) 4C086 AA04 DA38 NA01 ZB33 ZC55 4H050 AA02 AC40 BA92

Claims (7)

[Claims] 1. Contacting 9- [2- (phosphonomethoxy) ethyl] adenine with chloromethylpivalate and trialkylamine in 1-methyl-2-pyrrolidinone and recovering adefovir dipivoxil. A method for preparing adefovir dipivoxil, comprising: 2. The method of claim 1, wherein the trialkylamine is triethylamine. 3. A step of contacting 1 molar equivalent of 9- [2- (phosphonomethoxy) ethyl] adenine with 5.6 to 56.8 molar equivalents of 1-methyl-2-pyrrolidinone. The method described in 2. 4. The method of claim 1, comprising the step of contacting 1 molar equivalent of 9- [2- (phosphonomethoxy) ethyl] adenine with 2-5 molar equivalents of triethylamine. 5. A method comprising the step of contacting 9- [2- (phosphonomethoxy) ethyl] adenine containing 0% to 2% salt with chloromethyl pivalate. 6. The salt is NaBr or KBr,
The method of claim 6. 7. A sodium alkoxide and 9- (2
9- [2- (diethylphosphonomethoxy) ethyl], including the step of contacting -hydroxyethyl) adenine
A method for preparing adenine.